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左炔诺孕酮宫内节育系统(曼月乐)说明书如下:

【药品名称】
商品名称：曼月乐
通用名称：左炔诺孕酮宫内节育系统
英文名称：Levonorgestrel  Intrauterine  System

【成份】
曼月乐主要成分为左炔诺孕酮。

【药物分类】
其它避孕药和用品

【性状】
曼月乐为白色至类白色筒状物，架在T状体上，外罩不透明的套管。T状体的一端上有一小环，小环上系有取出尾丝，另一端为两臂。曼月乐应无异物。

【适应症】
避孕；特发性月经过多。

【规格】
含左炔诺孕酮52mg/个（20微克/24小时）

【用法用量】
左炔诺孕酮宫内节育系统应放置于宫腔内。一次放置可维持5年有效。
体内溶解速率开始时约为20ug/24hr，5年后降为约11ug/24hr。左炔诺孕酮在5年时间内的平均溶解速率约为14ug/24hr。

【不良反应】
不良反应在放置后的前几个月内更为常见，并随使用时间的延长而逐渐消失。
妇女在使用左炔诺孕酮宫内节育系统期间发生月经出血类型的改变属于正常现象。这些改变可以包括点滴出血、月经期缩短或延长、不规则出血、月经过少、闭经、出血过多、腰痛和痛经。
在使用的前6个月内，点滴出血的平均天数逐渐从9天减少到4天。在使用的前3个月内，有出血延长（超过8天）的妇女的百分率从20％降到3％。使用第1年的临床研究中，17％的妇女有至少3个月的闭经。
曾报告有下列的不良反应，按照发生频率依次为：头痛（亦包括罕见的偏头痛）、下腹痛、腰痛、皮肤疾病（如痤疮、皮疹及瘙痒）、阴道分泌物、乳痛和其他良性乳房情况、阴道炎、抑郁和其他情绪改变、恶心及水肿。其他不良反应如体重增加、脱发或油脂性头发、多毛症及腹胀也有个别病例报告。
万一避孕失败有可能为异位妊娠。使用左炔诺孕酮宫内节育系统者有可能发生严重的盆腔炎症，但发生率很低。整个节育系统或部份有可能穿透子宫壁。可能发生卵泡增大（功能性卵巢囊肿），在使用左炔诺孕酮宫内节育系统的妇女中约有12％被诊断出卵泡增大。

【禁忌】
如果妇女有下列任何一种情况，不应使用左炔诺孕酮宫内节育系统：已知或怀疑妊娠；现患盆腔炎或盆腔炎复发；下生殖道感染；产后子宫内膜炎；过去3个月内有感染性流产；宫颈炎；宫颈非典型增生；子宫或宫颈恶性病变；先天性或获得性子宫异常，包括使宫腔扭曲的肌瘤；增加感染易感性的疾病；急性肝脏疾病或肝肿瘤；对该系统组成成分过敏。

【警告】
如果存在或首次出现下列任何一种情况，需谨慎使用或考虑将曼月乐从宫腔取出：偏头痛，渐进性偏头痛，局灶性偏头痛伴不对称视力丧失或其它症状提示有暂时性脑缺血；罕见的严重头痛；黄疸；明显的血压升高；确诊或可疑的激素依赖性肿瘤，包括乳腺癌、影响血液的恶性病变或白血病；严重的动脉性疾病如卒中或心肌梗塞；血栓性静脉炎。如有提示视网膜栓塞的症状或体征：原因不明的部分或完全性视力丧失、眼球突出或复视、视乳头水肿或视网膜血管病变，应立即给予适当的处理。

【注意事项】
左炔诺孕酮宫内节育系统经向专家咨询后可以谨慎地使用，如有下列任何一种情况存在或使用期间首次出现，应考虑取出该系统：偏头痛、局灶性偏头痛伴有不对称的视力丧失或提示有暂时性脑缺血的其他症状；特别严重的头痛；黄疸；明显增高的血压；肯定或可疑的激素依赖性肿瘤包括乳腺癌；严重的动脉性疾病如卒中、或心肌梗塞。
一些近期的流行病学研究表明，使用单一孕激素避孕药的妇女中，静脉血栓栓塞的危险有轻度增加，但是结果没有统计学意义。然而，如果出现血栓形成的症状或体征，应立即采取恰当的诊断和治疗措施。静脉或动脉血栓形成的症状包括：单侧腿痛及/或肿胀；突发的严重胸痛，不论其是否向左臂放射；突发的气短；突发的咳嗽；任何异常、严重、持久的头痛；突发部分或全部视力丧失；复视；语言含混不清或失语；眩晕、伴或不伴局部抽搐的虚脱、突然影响机体一侧或一部分的虚弱感或非常明显的麻木；运动障碍；急腹症。提示有视网膜血栓形成的症状或体征有：无法解释的部分或全部视力丧失，发生眼突出或复视、视乳头水肿、或视网膜血管病变。
关于静脉曲张与浅表性血栓性静脉炎在静脉血栓栓塞中的可能作用没有一致意见。
左炔诺孕酮宫内节育系统可以谨慎地用于有先天性心脏病或有感染性心内膜炎危险的瓣膜性心脏病的妇女。这些患者放置或取出IUS时应给予预防性的抗生素。
低剂量的左炔诺孕酮可能影响糖耐量，所以糖尿病妇女使用左炔诺孕酮宫内节育系统时应监测血糖浓度。
不规则出血可能掩盖了子宫内膜息肉或癌的一些症状和体征，对于这些病例应考虑诊断性措施。
左炔诺孕酮宫内节育系统不是年轻未产妇的方法，也不适合子宫非常萎缩的绝经后妇女。
放置与取出/更换
放置前，必须告诉妇女左炔诺孕酮宫内节育系统的效果、危险与不良反应。应作体格检查，包括盆腔检查、乳腺检查及宫颈涂片。应该除外妊娠和性传播疾病，生殖道感染必须彻底治疗。应确定子宫的位置和宫腔的大小。为了保证子宫内膜均匀地暴露于孕激素下、防止脱落和达到的效果，宫内节育系统的基准定位特别重要。因此，应认真遵循放置说明。放置后4-12周必须随访检查妇女，此后每年1次，或者如有临床需要可增加随访检查的次数。
生育年龄的妇女，左炔诺孕酮宫内节育系统必须在月经开始的7天以内放入宫腔。用一新系统更换左炔诺孕酮宫内节育系统可以在周期的任何时间进行。该系统也可以在早孕流产后立即放置。产后放置应推迟到分娩后6周，左炔诺孕酮宫内节育系统不适合作为性交后避孕方法。
因为在治疗的前几个月中不规则出血/点滴出血很常见，所以推荐在放置左炔诺孕酮宫内节育系统以前应除外内膜病理情况。如果妇女在早前为了避孕已经放置了左炔诺孕酮宫内节育系统并愿继续使用，在开始雌激素替代治疗后如出现异常出血，则应除外子宫内膜的病理学改变。如果在长期的放置期间发生不规则出血，应采取适当的诊断措施。
左炔诺孕酮宫内节育系统可以用钳子夹住尾丝轻柔牵拉取出。如果看不见尾丝，而系统是在宫腔内，可以使用细的持物钳取出。但这可能需要扩张宫颈管。
该系统应在5年后取出。如果使用者希望继续使用同一方法，可以在取出的同时放入一个新的系统。
生育年龄妇女如果不希望妊娠，只要仍然有月经周期，取出应该在月经期进行。如果是在月经周期的中期取出该系统，而妇女在取出后1周内有性生活，则她有妊娠的危险，除非在取出后当即放入一个新的系统。
放置与取出时可能会有一些疼痛与出血。手术可能由于血管迷走神经反应而促发晕厥，或使癫痫患者抽搐发作。
月经过少/闭经
生育年龄的妇女，约20％的使用者逐渐发生月经过少及/或闭经。如果停经6周应考虑妊娠的可能性。没有必要对闭经患者重复妊娠试验，除非有其他妊娠征象。
盆腔感染
放置管有助于防止左炔诺孕酮宫内节育系统在放置过程中受到微生物的污染，并且左炔诺孕酮宫内节育系统放置器的设计将感染的危险减到了小。使用含铜宫内节育器时，盆腔感染率发生在放置后第1个月内，以后逐渐减少。某些研究提示，左炔诺孕酮宫内节育系统使用者的盆腔感染率低于带含铜宫内节育器者。盆腔感染性疾病的已知危险因素是多个性伙伴。盆腔感染可以影响生育并增加异位妊娠的危险。
如果妇女出现复发的子宫内膜炎或盆腔感染，或严重的急性感染，或经过几天的治疗没有好转，那么必须取出左炔诺孕酮宫内节育系统。
有感染可能时，即使症状不像，推荐作细菌学检查及监测。
脱落
任何IUD部分或全部脱落的症状包括出血或疼痛。然而，有时该系统可能从宫腔排出而妇女没有注意到，部分脱落可能降低左炔诺孕酮宫内节育系统的有效性。因为左炔诺孕酮宫内节育系统减少月经出血量，如果月经出血量增多，可能提示发生脱落。
必须取出移位的左炔诺孕酮宫内节育系统。可以同时放置一个新的系统。
应当指导妇女如何检查曼月乐的尾丝。
穿孔
罕见地，宫内节育器可能引起子宫体或宫颈的穿孔或穿透，通常发生在放置时。这种情况下，必须取出该系统。
异位妊娠
既往有异位妊娠、输卵管手术或盆腔感染史的妇女，异位妊娠的危险较高。如果发生下腹痛－特别是伴有月经过期、或者闭经的妇女开始出血，应该考虑异位妊娠的可能性。左炔诺孕酮宫内节育系统使用者的异位妊娠率为0.06/100妇女年。该率显著地低于未使用任何避孕方法的妇女的估计的异位妊娠率1.2-1.6。
尾丝丢失
随诊检查时如果在宫颈处未能见到尾丝，必须除外妊娠。尾丝可能被牵入子宫或宫颈管内，下次月经期可能会又出现。如果除外了妊娠，使用适当的器具轻轻地探查通常可以在局部找到尾丝。如果找不到，该系统可能已经被排出。可使用超声诊断以正确定位该系统。如果没有超声或者超声不清楚，可使用X线来定位左炔诺孕酮宫内节育系统。
延迟的卵泡闭锁
因为左炔诺孕酮宫内节育系统的避孕作用主要取决于局部作用，育龄妇女常于排卵周期发生卵泡破裂。有时卵泡闭锁延迟而卵泡生成继续进行。临床上这些增大的卵泡不能与卵巢囊肿区分。约12％使用左炔诺孕酮宫内节育系统的妇女被诊断出有卵泡增大。这些卵泡绝大多数没有症状，虽然某些可能伴有盆腔痛或性交痛。
大多数病例增大的卵泡在2-3个月的观察期内自发消失。如果没有消失，应继续超声监测，并采用其他的诊断治疗措施。罕见情况下可能需要外科手术。

【孕妇及哺乳期妇女用药】
妊娠：
左炔诺孕酮宫内节育系统不能用于正在妊娠或可疑妊娠的情况。
在位左炔诺孕酮宫内节育系统合并妊娠非常罕见。但是如果左炔诺孕酮宫内节育系统脱出，必须在咨询医生前使用其他避孕方法。
某些妇女在使用左炔诺孕酮宫内节育系统期间可能停经。停经不一定是妊娠的征象。如果妇女停经并有其他妊娠症状（如恶心、倦怠、乳房胀痛），她应该去看医生作检查及妊娠试验。
如果妇女在使用左炔诺孕酮宫内节育系统期间发生妊娠，建议取出左炔诺孕酮宫内节育系统，因为任何宫内节育器留置宫腔可能增加流产和早产的危险。取出左炔诺孕酮宫内节育系统或探查宫腔可能造成自然流产。如果宫内节育器不能很容易地被取出，可考虑终止妊娠。如果妇女希望继续妊娠而该系统又不能取出，则应该将危险及婴儿早产的可能结局告诉妇女。必须严密监测这样的妊娠过程。应该除外异位妊娠。应指导妇女报告提示有妊娠并发症的所有症状，如伴有发热的痉挛性腹痛。
因为宫腔内给药，并且局部激素暴露，致畸性（特别是男性化）不能完全除外。由于左炔诺孕酮宫内节育系统避孕的性，使用左炔诺孕酮宫内节育系统情况下的妊娠结局的临床经验有限，但应告诉妇女，迄今，还没有因使用左炔诺孕酮宫内节育系统发生在位妊娠并且妊娠继续到足月而引起的出生缺陷的证据。
哺乳：
使用左炔诺孕酮宫内节育系统的左炔诺孕酮的日剂量及血浆浓度低于任何其他的激素避孕方法，但是在使用左炔诺孕酮宫内节育系统的哺乳妇女的乳汁中有小量左炔诺孕酮存在。哺乳期不推荐激素避孕法，但单一孕激素方法被认为是仅次于非激素避孕方法类的一种选择。哺乳期使用左炔诺孕酮宫内节育系统极少发生子宫出血。没有观察到产后6周以后使用任何单一孕激素方法对婴儿生长发育的有害影响。单一孕激素方法未显示影响乳汁的数量或质量。

【儿童用药】
左炔诺孕酮宫内节育系统的使用与儿童无关。

【老年患者用药】
左炔诺孕酮宫内节育系统不适用于老年人。

【药物相互作用】
激素避孕药的作用可能受到肝酶诱导剂的影响，包括扑米酮、巴比妥酸盐、苯妥英、卡马西平、利福平及奥卡西平；灰黄霉素也属可疑。没有研究过这些药物对左炔诺孕酮宫内节育系统的避孕作用的影响，但是由于左炔诺孕酮主要是局部的作用机制，一般认为不太重要。

【用药须知】
左炔诺孕酮宫内节育系统以无菌包装供应，不得在放置前打开包装。打开的产品应注意无菌操作。无菌包装的密封处如有破损，这套IUS应按药物废弃物予以丢弃。取出的IUS同样应按药物废弃物处理，因为它可能含有残余的激素。放置器应按医院废弃物处理，外层的包装箱及内层的包装袋可按家庭废弃物处理。放置的特殊须知见包装内。
因为放置技术与其他宫内节育器有所不同，应特别强调进行正确放置技术的培训。

【曼月乐药理作用】
左炔诺孕酮是一种孕激素，在妇科学上有多种用途：如用作口服避孕药与激素替代治疗中的孕激素成分，或单独用于避孕的仅含有孕激素的避孕药及皮下埋植剂。左炔诺孕酮也可通过宫内释放系统在宫腔内给药。这样，由于激素直接释放进入靶器官，就可以使用很低的日剂量。
左炔诺孕酮宫内节育系统在宫腔内主要发挥局部孕激素作用。子宫内膜的高左炔诺孕酮浓度抑制了雌激素受体在子宫内膜的合成，使子宫内膜对血循环中的雌二醇失去敏感性，从而发挥强力的内膜增生拮抗作用。使用左炔诺孕酮宫内节育系统期间，可以观察到内膜的形态学变化和微弱的局部异物反应。宫颈粘液变为粘稠阻止了精子通过宫颈管。子宫和输卵管的局部内环境抑制了精子的活动与功能，防止了受精。在某些妇女中，排卵亦受到抑制。
对其避孕效果的研究主要是将左炔诺孕酮宫内节育系统与各种含铜宫内节育器进行比较。迄今左炔诺孕酮宫内节育系统的使用达13000妇女1年，总的妊娠率为0.16/100妇女年。
使用左炔诺孕酮宫内节育系统不影响以后的生育力。约有80％希望妊娠的妇女在取出系统后12个月内受孕。
月经类型是左炔诺孕酮直接作用于子宫内膜的结果，而并不反映卵巢的周期。出血类型不同的妇女在卵泡发育、排卵或雌二醇和孕酮产生方面并无明显的不同。在对抗子宫内膜增生的过程中，使用的初几个月可能出现点滴出血的初始性增加。然后，在左炔诺孕酮宫内节育系统使用期间，由于对子宫内膜很强的抑制作用，使月经出血持续时间及出血量减少。月经血量减少常发展为月经过少或闭经。即使左炔诺孕酮宫内节育系统的使用者出现闭经，卵巢功能仍是正常的，雌二醇水平也能维持原状。
左炔诺孕酮宫内节育系统可以有效地用于特发性月经过多的治疗。月经过多的妇女在使用左炔诺孕酮宫内节育系统后3个月内，月经失血量减少88％。对于因粘膜下肌瘤引起的月经过多可能疗效欠佳。出血减少增加了血红蛋白的浓度。左炔诺孕酮宫内节育系统还可缓解痛经。

【药代动力学】
放置左炔诺孕酮宫内节育系统后，左炔诺孕酮在宫腔内的初始释放量为20ug/24hr。这使生育年龄妇女放置后初几周的血浆左炔诺孕酮浓度稳定在0.4-0.6nmol/L（150-200pg/mL）水平。年轻妇女长期使用12，24和60个月后，左炔诺孕酮血浆浓度分别为180±66pg/mL，192±140pg/mL和159±60pg/mL。因为药物的血浆浓度很低，所以孕激素的全身影响已降至小。
对于左炔诺孕酮本身的药代动力学已有广泛的研究和文献报告。口服给予左炔诺孕酮吸收迅速完全，生物利用度约为90％。左炔诺孕酮与血清白蛋白和性激素结合球蛋白（SHBG）结合。其相对分布（游离、与白蛋白结合、与SHBG结合）取决于血清SHBG浓度。除了分别有47.5％及50％与SHBG及白蛋白结合外，仅约2.5％的总血清药物水平呈游离状态。据报告，左炔诺孕酮的平均分布容积约为137L，血清的代谢清除率约为5.7L/hr。单次给药后，左炔诺孕酮的终末半衰期约在14-20小时范围内。左炔诺孕酮以代谢物形式从尿与粪便中等量排泄。代谢物只有微弱的或没有药理活性。尿中的主要代谢物为四氢炔诺孕酮，其占给予放射标记的左炔诺孕酮后从尿中回收到的放射性物质的约25％。
大约0.1％的母体左炔诺孕酮剂量可以经乳汁转移给哺乳婴儿。

【毒理研究】
左炔诺孕酮是一种众所周知的具有抗雌激素活性的孕激素。已有大量资料阐明了全身给药后的安全性。一项对猴子子宫腔内给予左炔诺孕酮12个月的研究肯定了它的局部药理作用和良好的局部耐受性，并且无全身毒性征象。兔子子宫腔内给予左炔诺孕酮后未见胚胎毒性。曼月乐的激素储库的弹性体组成成分，聚乙烯材料以及弹性体与左炔诺孕酮的联合体的安全性评估，并根据两者标准的体外、体内遗传毒理学测试系统评价和在小鼠、豚鼠、兔子与体外检测系统的生物相容性试验，均未显示曼月乐有生物不相容性。

【贮藏】
曼月乐应贮藏于15-30°C，避光防潮。

【有效期】
3年。

【生产企业】
生产厂商（英文）BayerScheringPharmaOy

MIRENA 
(levonorgestrel-releasing) Intrauterine System

DESCRIPTION

Mirena (levonorgestrel-releasing intrauterine system) contains 52 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately 20 mcg/day of LNG.

Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in Mirena, has a molecular weight of 312.4, a molecular formula of C21H28O2, and the following structural formula:

Mirena

Mirena consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The reservoir consists of a white or almost white cylinder, made of a mixture of levonorgestrel and silicone (polydimethylsiloxane), containing a total of 52 mg levonorgestrel. The reservoir is covered by a semi-opaque silicone (polydimethylsiloxane) membrane. The T-body is 32 mm in both the horizontal and vertical directions. The polyethylene of the T-body is compounded with barium sulfate, which makes it radiopaque. A monofilament brown polyethylene removal thread is attached to a loop at the end of the vertical stem of the T-body. The polyethylene of the removal thread contains iron oxide as a colorant (see Figure 10).

The components of Mirena, including its packaging, are not manufactured using natural rubber latex.

Figure 10: Mirena

Inserter

Mirena is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Mirena into the uterine cavity, consists of a symmetric two-sided body and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. The outer diameter of the insertion tube is 4.4 mm. The vertical stem of Mirena is loaded in the insertion tube at the tip of the inserter. The arms are pre-aligned in the horizontal position. The removal threads are contained within the insertion tube and handle. Once Mirena has been placed, the inserter is discarded.

Figure 11: Diagram of Inserter

Indications & Dosage

INDICATIONS

Mirena is indicated for intrauterine contraception for up to 5 years.

Mirena is also indicated for the treatment of heavy menstrual bleeding in women who choose to use intrauterine contraception as their method of contraception.

Mirena is recommended for women who have had at least one child.

The system should be replaced after 5 years if continued use is desired.

DOSAGE AND ADMINISTRATION

Mirena contains 52 mg of levonorgestrel (LNG). Initially, LNG is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years.

Mirena must be removed by the end of the fifth year and can be replaced at the time of removal with a new Mirena if continued contraceptive protection is desired.

Mirena is supplied within an inserter in a sterile package (see Figure 1) that must not be opened until required for insertion [see DESCRIPTION]. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [seeWARNINGS AND PRECAUTIONS].

Insertion Instructions

· A complete medical and social history should be obtained to determine conditions that might influence the selection of a levonorgestrel-releasing intrauterine system (LNG IUS) for contraception. If indicated, perform a physical examination, and appropriate tests for any forms of genital or other sexually transmitted infections. [See CONTRAINDICATIONS andWARNINGS AND PRECAUTIONS]

· Follow the insertion instructions Exactly as described in order to ensure proper placement and avoid premature release of Mirena from the inserter. Once released, Mirena cannot be re-loaded.

· Mirena should be inserted by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Mirena.

· Insertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia), or with seizure in an epileptic patient, especially in patients with a predisposition to these symptoms. Consider administering analgesics prior to insertion.

Timing Of Insertion

· Insert Mirena into the uterine cavity during the first seven days of the menstrual cycle or immediately after a first trimester abortion. Back up contraception is not needed when Mirena is inserted as directed.

· Postpone postpartum insertion and insertions following second trimester abortions a minimum of six weeks or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see WARNINGS AND PRECAUTIONS].

Tools For Insertion

Preparation

· Gloves

· Speculum

· Sterile uterine sound

· Sterile tenaculum

· Antiseptic solution, applicator

Procedure

· Sterile gloves

· Mirena with inserter in sealed package

· Instruments and anesthesia for paracervical block, if anticipated

· Consider having an unopened backup Mirena available

· Sterile, sharp curved scissors

Preparation For Insertion

· Exclude pregnancy and confirm that there are no other contraindications to the use of Mirena.

· Ensure that the patient understands the contents of the Patient Information Booklet and obtain the signed patient informed consent located on the last page of the Patient Information Booklet.

· With the patient comfortably in lithotomy position, do a bimanual exam to establish the size, shape and position of the uterus.

· Gently insert a speculum to visualize the cervix.

· Thoroughly cleanse the cervix and vagina with a suitable antiseptic solution.

· Prepare to sound the uterine cavity. Grasp the upper lip of the cervix with a tenaculum forceps and gently apply traction to stabilize and align the cervical canal with the uterine cavity. Perform a paracervical block if needed. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. The tenaculum should remain in position and gentle traction on the cervix should be maintained throughout the insertion procedure.

· Gently insert a uterine sound to check the patency of the cervix, measure the depth of the uterine cavity in centimeters, confirm cavity direction, and detect the presence of any uterine anomaly. If you encounter difficulty or cervical stenosis, use dilatation, and not force, to overcome resistance. If cervical dilatation is required, consider using a paracervical block.

· The uterus should sound to a depth of 6 to 10 cm. Insertion of Mirena into a uterine cavity less than 6 cm by sounding may increase the incidence of expulsion, bleeding, pain, perforation, and possibly pregnancy.

Insertion Procedure

Proceed with insertion only after completing the above steps and ascertaining that the patient is appropriate for Mirena. Ensure use of aseptic technique throughout the entire procedure.

Step 1-Opening of the Package

· Open the package (Figure 1). The contents of the package are sterile.

Figure 1: Opening the Mirena Package

· Using sterile gloves lift the handle of the sterile inserter and remove from the sterile package.

Step 2-Load Mirena Into the Insertion Tube

· Push the slider forward as far as possible in the direction of the arrow thereby moving the insertion tube over the Mirena T-body to load Mirena into the insertion tube (Figure 2). The tips of the arms will meet to form a rounded end that extends slightly beyond the insertion tube.

Figure 2: Move slider all the way to the forward position to load Mirena

· Maintain forward pressure with your thumb or forefinger on the slider. DO NOT move the slider downward at this time as this may prematurely release the threads of Mirena. Once the slider is moved below the mark, Mirena cannot be re-loaded.

Step 3-Setting the Flange

· Holding the slider in this forward position, set the upper edge of the flange to correspond to the uterine depth (in centimeters) measured during sounding (Figure 3).

Figure 3: Setting the flange

Step 4-Mirena Is Now Ready To Be Inserted

· Continue holding the slider in this forward position. Advance the inserter through the cervix until the flange is approximately 1.5-2 cm from the cervix and then pause (Figure 4).

Figure 4: Advancing insertion tube until flange is 1.5 to 2 cm from the cervix

Do not force the inserter. If necessary, dilate the cervical canal.

Step 5-Open the Arms

· While holding the inserter steady, move the slider down to the mark to release the arms of Mirena (Figure 5). Wait 10 seconds for the horizontal arms to open completely.

Figure 5: Move the slider back to the mark to release and open the arms

Step 6-Advance to Fundal Position

· Advance the inserter gently towards the fundus of the uterus until the flange touches the cervix. If you encounter fundal resistance do not continue to advance. Mirena is now in the fundal position (Figure 6). Fundal positioning of Mirena is important to prevent expulsion.

Figure 6: Move Mirena into the fundal position

Step 7-Release Mirena and Withdraw the Inserter

· Holding the entire inserter firmly in place, release Mirena by moving the slider all the way down (Figure 7).

Figure 7. Move the slider all the way down to release Mirena from the insertion tube

· Continue to hold the slider all the way down while you slowly and gently withdraw the inserter from the uterus.

· Using a sharp, curved scissor, cut the threads perpendicular, leaving about 3 cm visible outside of the cervix [cutting threads at an angle may leave sharp ends (Figure 8)]. Do not apply tension or pull on the threads when cutting to prevent displacing Mirena.

Figure 8: Cutting the threads

Mirena insertion is now complete. Prescribe analgesics, if indicated. Keep a copy of the Consent Form with lot number for your records.

Important Information To Consider During Or After Insertion

· If you suspect that Mirena is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Mirena if it is not positioned completely within the uterus. A removed Mirena must not be re-inserted.

· If there is clinical concern, exceptional pain or bleeding during or after insertion, appropriate steps (such as physical examination and ultrasound) should be taken immediately to exclude perforation.

Patient Follow-up

· Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.

Removal Of Mirena

Timing of Removal

· Mirena should not remain in the uterus after 5 years.

· If pregnancy is not desired, the removal should be carried out during menstruation, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle, consider starting a new contraceptive method a week prior to removal. If removal occurs at other times during the cycle and the woman has had intercourse in the week prior to removal, she is at risk of pregnancy. [See Continuation of Contraception after Removal]

Tools for Removal

Preparation

· Gloves

· Speculum

Procedure

· Sterile forceps

Removal Procedure

· Remove Mirena by applying gentle traction on the threads with forceps. (Figure 9).

Figure 9: Removal of Mirena

· If the threads are not visible, determine location of Mirena by ultrasound [see WARNINGS AND PRECAUTIONS].

· If Mirena is found to be in the uterine cavity on ultrasound exam, it may be removed using a narrow forceps, such as an alligator forceps. This may require dilation of the cervical canal. After removal of Mirena, examine the system to ensure that it is intact.

· Removal may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, or a seizure in an epileptic patient).

Continuation Of Contraception After Removal

· If pregnancy is not desired and if a woman wishes to continue using Mirena, a new system can be inserted immediately after removal any time during the cycle.

· If a patient with regular cycles wants to start a different birth control method, time removal and initiation of new method to ensure continuous contraception. Either remove Mirena during the first 7 days of the menstrual cycle and start the new method immediately thereafter or start the new method at least 7 days prior to removing Mirena if removal is to occur at other times during the cycle.

· If a patient with irregular cycles or amenorrhea wants to start a different birth control method, start the new method at least 7 days before removal.

HOW SUPPLIED

Dosage Forms And Strengths

Mirena is a LNG-releasing IUS consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 52 mg LNG.

Storage And Handling

Mirena (levonorgestrel-releasing intrauterine system), containing a total of 52 mg LNG, is available in a carton of one sterile unit NDC# 50419-423-01.

Mirena is supplied sterile. Mirena is sterilized with ethylene oxide. Do not resterilize. For single use only. Do not use if the inner package is damaged or open. Insert before the end of the month shown on the label.

Store at 25°C (77°F); with excursions permitted between 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981. Manufactured in Finland. Revised: Dec 2016

Side Effects

SIDE EFFECTS

The following serious or otherwise important adverse reactions are discussed in elsewhere in the labeling:

· Ectopic Pregnancy [see WARNINGS AND PRECAUTIONS]

· Intrauterine Pregnancy [see WARNINGS AND PRECAUTIONS]

· Group A Streptococcal Sepsis (GAS) [see WARNINGS AND PRECAUTIONS]

· Pelvic Inflammatory Disease [see WARNINGS AND PRECAUTIONS]

· Alterations of Bleeding Patterns [see WARNINGS AND PRECAUTIONS]

· Perforation [see WARNINGS AND PRECAUTIONS]

· Expulsion [see WARNINGS AND PRECAUTIONS]

· Ovarian Cysts [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies 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.

The data provided reflect the experience with the use of Mirena in the adequate and well-controlled studies as well as in the supportive and uncontrolled studies for contraception and heavy menstrual bleeding (n=5,091). The data cover more than 12,101 women-years of exposure, mainly in the contraception studies (11,761 women-years). The frequencies of reported adverse drug reactions represent crude incidences.

The most common adverse reactions ( ≥ 10% users) are alterations of menstrual bleeding patterns [including unscheduled uterine bleeding (31.9%), decreased uterine bleeding (23.4%), increased scheduled uterine bleeding (11.9%), and female genital tract bleeding (3.5%)], abdominal/pelvic pain(22.6%), amenorrhea (18.4%), headache/migraine (16.3%), genital discharge (14.9%), and vulvovaginitis (10.5%). Adverse reactions reported in ≥ 5% of users are shown in Table 1.

Table 1 : Adverse Reactions ≥ 5% Reported in Clinical Trials with Mirena

Other adverse reactions occurring in < 5% of subjects include alopecia, (partial and complete) device expulsion, hirsutism, nausea, and PID/endometritis.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Mirena. 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.

· Arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli, deep vein thrombosis and stroke

· Device breakage

· Hypersensitivity (including rash, urticaria and angioedema)

· Increased blood pressure

Drug Interactions

DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with Mirena.

Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the serum concentrations of progestins.

Some drugs or herbal products that may decrease the serum concentration of LNG include:

· Barbiturates

· Bosentan

· Carbamazepine

· Efavirenz

· Felbamate

· Griseofulvin

· Nevirapine

· Oxcarbazepine

· Phenytoin

· Rifabutin

· Rifampin

· St. John's wort

· Topiramate

Significant changes (increase or decrease) in the serum concentrations of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Consult the labeling of all concurrently used drugs to obtain further information about interactions with Mirena or the potential for enzyme alterations.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Ectopic Pregnancy

Evaluate women for ectopic pregnancy if they become pregnant with Mirena in place because the likelihood of a pregnancy being ectopic is increased with Mirena. Up to half of pregnancies that occur with Mirena in place are likely to be ectopic. Also consider the possibility of ectopic pregnancy in the case of lower abdominal pain, especially in association with missed periods or if an amenorrheic woman starts bleeding.

The incidence of ectopic pregnancy in clinical trials with Mirena, which excluded women with a history of ectopic pregnancy, was approximately 0.1% per year. The risk of ectopic pregnancy, in women who have a history of ectopic pregnancy and use Mirena is unknown. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy. Ectopic pregnancy may result in loss of fertility.

Intrauterine Pregnancy

If pregnancy occurs while using Mirena, remove Mirena because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Mirena or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Mirena, consider the following:

Septic Abortion

In patients becoming pregnant with an IUD in place, septic abortion -with septicemia, septic shock, and death -may occur.

Continuation Of Pregnancy

If a woman becomes pregnant with Mirena in place and if Mirena cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Mirena increases the risk of miscarriage, sepsis, premature labor and premature delivery. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy.

Long-term Effects And Congenital Anomalies

When pregnancy continues with Mirena in place, long-term effects on the offspring are unknown. Congenital anomalies in live births have occurred infrequently. No clear trend towards specific anomalies has been observed. Because of the local exposure of the fetus to LNG, the possibility of teratogenicity following exposure to Mirena cannot be completely excluded. Some observational data support a small increased risk of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception. Whether these data apply to Mirena is unknown.

Sepsis

Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of Mirena. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Mirena is essential in order to minimize serious infections such as GAS.

Pelvic Infection

Pelvic Inflammatory Disease (PID)

Mirena is contraindicated in the presence of known or suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy [see CONTRAINDICATIONS]. IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, total combined upper genital infections were reported in 3.5% of Mirena users. More specifically, endometritis was reported in 2.1%, PID in 0.6%, and all other upper genital infections in ≤ 0.5% of women overall. These infections occurred more frequently within the first year. In a clinical trial with other IUDs1 and a clinical trial with an IUD similar to Mirena, the highest rate occurred within the first month after insertion.

Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Mirena in cases of recurrentendometritis or PID, or if an acute pelvic infection is severe or does not respond to treatment.

Women At Increased Risk For PID

PID is often associated with a sexually transmitted infection, and Mirena does not protect against sexually transmitted infection. The risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID are at increased risk for a recurrence or re-infection. In particular, ascertain whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse).

Asymptomatic PID

PID may be asymptomatic but still result in tubal damage and its sequelae.

Treatment Of PID

Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained and antibiotic therapy should be initiated promptly. Removal of Mirena after initiation of antibiotic therapy is usually appropriate. Guidelines for PID treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia.

Actinomycosis

Actinomycosis has been associated with IUDs. Symptomatic women should have Mirena removed and should receive antibiotics. The significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD user is unknown, and so this finding alone does not always require Mirena removal and treatment. When possible, confirm a Pap smear diagnosis with cultures.

Irregular Bleeding And Amenorrhea

Mirena can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first three to six months of Mirena use, the number of bleeding and spotting days may be increased and bleeding patterns may be irregular. Thereafter the number of bleeding and spotting days usually decreases but bleeding may remain irregular. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should be taken to rule out endometrial pathology.

Amenorrhea develops in approximately 20% of Mirena users by one year. The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the onset of previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain [see Clinical Studies].

In most women with heavy menstrual bleeding, the number of bleeding and spotting days may also increase during the initial months of therapy but usually decrease with continued use; the volume of blood loss per cycle progressively becomes reduced [see Clinical Studies].

Perforation

Perforation (total or partial, including penetration/embedment of Mirena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. Perforation may reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during clinical trials, which excluded breast-feeding women, was < 0.1%.

If perforation occurs, locate and remove Mirena. Surgery may be required. Delayed detection or removal of Mirena in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion ofadjacent viscera.

The risk of perforation may be increased if Mirena is inserted when the uterus is fixed retroverted or not completely involuted. Delay Mirena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion.

A large postmarketing safety study conducted in Europe over a 1-year observational period reported that lactation at the time of insertion of an IUD/IUS was associated with an increased risk of perforation. For Mirena users, the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1.0 per 1,000 insertions for non-lactating women.

Expulsion

Partial or complete expulsion of Mirena may occur resulting in the loss of contraceptive protection. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Mirena typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. The risk of expulsion may be increased when the uterus is not completely involuted. In clinical trials, a 4.5% expulsion rate was reported over the 5-year study duration.

Delay Mirena insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Mirena. If expulsion has occurred, Mirena may be replaced within 7 days after the onset of a menstrual period, after pregnancy has been ruled out.

Ovarian Cysts

Because the contraceptive effect of Mirena is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena. Sometime atresia of the follicle is delayed and the follicle may continue to grow. Ovarian cysts have been reported in approximately 8% of women using Mirena. Most of these cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.

In most cases the ovarian cysts disappear spontaneously during two to three months observation. Evaluate persistent ovarian cysts. Surgical intervention is not usually required.

Breast Cancer

Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception because some breast cancers are hormone-sensitive [see CONTRAINDICATIONS].

Spontaneous reports of breast cancer have been received during postmarketing experience with Mirena. Observational studies of the risk of breast cancer with use of a LNG-releasing IUS do not provide conclusive evidence of increased risk.

Clinical Considerations For Use And Removal

Use Mirena with caution after careful assessment if any of the following conditions exist, and consider removal of the system if any of them arise during use:

· Coagulopathy or use of anticoagulants

· Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia

· Exceptionally severe headache

· Marked increase of blood pressure

· Severe arterial disease such as stroke or myocardial infarction

In addition, consider removing Mirena if any of the following conditions arise during use [see CONTRAINDICATIONS]:

· Uterine or cervical malignancy

· Jaundice

If the threads are not visible or are significantly shortened they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced (for example, expelled or perforated the uterus) [see WARNINGS AND PRECAUTIONS]. Exclude pregnancy and verify the location of Mirena, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. If Mirena is displaced, remove it. A new Mirena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Mirena is in place with no evidence of perforation, no intervention is indicated.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)

· Sexually Transmitted Infections: Counsel the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).

· Risk of Ectopic Pregnancy: Inform the patient about the risks of ectopic pregnancy, including the loss of fertility. Teach her to recognize and report to her healthcare provider promptly any symptoms of ectopic pregnancy. [See WARNINGS AND PRECAUTIONS]

· Pregnancy or Suspected Pregnancy: Counsel the patient to inform her healthcare provider if she determines or suspects she is pregnant with Mirena in place.

· Pelvic Infection: Inform the patient about the possibility of pelvic inflammatory disease (PID) and that PID can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach the patient to recognize and report to her healthcare provider promptly any symptoms of PID. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. [See WARNINGS AND PRECAUTIONS]

· Irregular Bleeding and Amenorrhea: Counsel the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. If her symptoms continue or are severe she should report them to her healthcare provider. [See WARNINGS AND PRECAUTIONS]

· Perforation and Expulsion: Counsel the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Caution her not to pull on the threads and displace Mirena. Inform her that there is no contraceptive protection if Mirena is displaced or expelled. [See WARNINGS AND PRECAUTIONS]

· Clinical Considerations for Use and Removal: Instruct the patient to contact her healthcare provider if she experiences any of the following:

o A stroke or heart attack

o Very severe or migraine headaches

o Unexplained fever

o Yellowing of the skin or whites of the eyes, as these may be signs of serious liver problems

o Pregnancy or suspected pregnancy

o Pelvic pain or pain during sex

o HIV positive seroconversion in herself or her partner

o Possible exposure to sexually transmitted infections (STIs)

o Unusual vaginal discharge or genital sores

o Severe vaginal bleeding or bleeding that lasts a long time, or if she misses a menstrual period

o Inability to feel Mirena's threads

Complete the Follow-up Reminder Card and give to the patient.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

[See WARNINGS AND PRECAUTIONS]

Use In Specific Populations

Pregnancy

The use of Mirena during an existing or suspected pregnancy is contraindicated. Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects. [SeeCONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]

Nursing Mothers

In general, no adverse effects of progestin-only contraceptives have been found on breastfeeding performance or on the health, growth, or development of the infant. Isolated postmarketing cases of decreased milk production have been reported. Small amounts of progestins were observed to pass into the breast milk of nursing mothers who used Mirena, resulting in detectable steroid levels in infant serum. [See WARNINGS AND PRECAUTIONS]

Pediatric Use

Safety and efficacy of Mirena have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated.

Geriatric Use

Mirena has not been studied in women over age 65 and is not approved for use in this population.

Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from Mirena [see CONTRAINDICATIONS].

Renal Impairment

No studies were conducted to evaluate the effect of renal disease on the disposition of LNG released from Mirena.

REFERENCES

1Farley T M M, Rosenberg M J, Rowe P J, Chen J, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992; 339:785-788.

Overdosage & Contraindications

OVERDOSE

No information provided.

CONTRAINDICATIONS

The use of Mirena is contraindicated when one or more of the following conditions exist:

· Pregnancy or suspicion of pregnancy; cannot be used for post-coital contraception [seeWARNINGS AND PRECAUTIONS]

· Congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity

· Acute pelvic inflammatory disease or a history of pelvic inflammatory disease unless there has been a subsequent intrauterine pregnancy [see WARNINGS AND PRECAUTIONS]

· Postpartum endometritis or infected abortion in the past 3 months

· Known or suspected uterine or cervical neoplasia

· Known or suspected breast cancer or other progestin-sensitive cancer, now or in the past

· Uterine bleeding of unknown etiology

· Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled

· Acute liver disease or liver tumor (benign or malignant)

· Conditions associated with increased susceptibility to pelvic infections [see WARNINGS AND PRECAUTIONS]

· A previously inserted intrauterine device (IUD) that has not been removed

· Hypersensitivity to any component of this product [see ADVERSE REACTIONS]

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

The local mechanism by which continuously released LNG enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated. Studies of Mirena and similar LNG IUS prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium.

Pharmacodynamics

Mirena has mainly local progestogenic effects in the uterine cavity. The high local levels of LNG2 lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.

Ovulation is inhibited in some women using Mirena. In a 1-year study, approximately 45% of menstrual cycles were ovulatory, and in another study after 4 years, 75% of cycles were ovulatory.

Pharmacokinetics

Absorption

Low doses of LNG are administered into the uterine cavity with the Mirena intrauterine delivery system. The initial release rate is approximately 20 mcg/day over the first 3 months tested (day 0 to day 90). It is reduced to approximately 18 mcg/day after 1 year and then decreases progressively to approximately 10 mcg/day after 5 years.

A stable serum concentration, without peaks and troughs, of LNG of 150-200 pg/mL occurs after the first few weeks following insertion of Mirena. LNG concentrations after long-term use of 12, 24, and 60 months were 180±66 pg/mL, 192±140 pg/mL, and 159±59 pg/mL, respectively.

Distribution

The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.

Metabolism

Following absorption, LNG is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG-containing contraceptive products. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4.

Excretion

About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of LNG after daily oral doses is approximately 17 hours.

Specific Populations

Pediatric: Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatric: Mirena has not been studied in women over age 65 and is not currently approved for use in this population.

Race: No studies have evaluated the effect of race on pharmacokinetics of Mirena.

Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Mirena.

Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Mirena.

Drug-Drug Interactions

No drug-drug interaction studies were conducted with Mirena [see DRUG INTERACTIONS].

Clinical Studies

Clinical Trials On Contraception

Mirena has been studied for safety and efficacy in two large clinical trials in Finland and Sweden. In study sites having verifiable data and informed consent, 1,169 women 18 to 35 years of age at enrollment used Mirena for up to 5 years, for a total of 45,000 women-months of exposure. Subjects had previously been pregnant, had no history of ectopic pregnancy, had no history of pelvic inflammatory disease over the preceding 12 months, were predominantly Caucasian, and over 70% of the participants had previously used IUDs (intrauterine devices). The reported 12-month pregnancy rates were less than or equal to 0.2 per 100 women (0.2%) and the cumulative 5-year pregnancy rate was approximately 0.7 per 100 women (0.7%).

About 80% of women wishing to become pregnant conceived within 12 months after removal of Mirena.

Clinical Trial On Heavy Menstrual Bleeding

The efficacy of Mirena in the treatment of heavy menstrual bleeding was studied in a randomized, open-label, active-control, parallel-group trial comparing Mirena (n=79) to an approved therapy, medroxyprogesterone acetate (MPA) (n=81), over 6 cycles. The subjects included reproductive-aged women in good health, with no contraindications to the drug products and with confirmed heavy menstrual bleeding ( ≥ 80 mL menstrual blood loss [MBL]) determined using the alkaline hematin method. Excluded were women with organic or systemic conditions that may cause heavy uterine bleeding (except small fibroids, with total volume not > 5 mL). Treatment with Mirena showed a statistically significantly greater reduction in MBL (see Figure 12) and a statistically significantly greater number of subjects with successful treatment (see Figure 13). Successful treatment was defined as proportion of subjects with (1) end-of-study MBL < 80 mL and (2) a ≥ 50% decrease in MBL from baseline to end-of-study.

Figure 12: Median Menstrual Blood Loss (MBL) by Time and Treatment

Figure 13. Proportion of Subjects with Successful Treatment

REFERENCES

2Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of LNG in women using a LNG-releasing IUD. Clinical Endocrinol 1982;17:529-536.

Medication Guide

PATIENT INFORMATION

Mirena® 
(mur-a-nah)
(levonorgestrel-releasing) Intrauterine System

Mirena does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).

Read this Patient Information carefully before you decide if Mirena is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women's health. If you have any questions about Mirena, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you.

What is Mirena?

· Mirena is a hormone-releasing system placed in your uterus by your healthcare provider to prevent pregnancy for up to 5 years.

· Mirena can also lessen menstrual blood loss in women who have heavy menstrual flow and who also want to use a birth control method that is placed in the uterus to prevent pregnancy.

· Mirena can be removed by your healthcare provider at any time.

· Mirena is recommended for women who have had at least one child.

Mirena is a small flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel that is often used in birth control pills. Because Mirena releases levonorgestrel into your uterus, only small amounts of the hormone enter your blood. Mirena does not contain estrogen.

Two thin threads are attached to the stem of Mirena. The threads are the only part of Mirena you can feel when Mirena is in your uterus; however, unlike a tampon string, the threads do not extend outside your body.

Mirena is small and flexible

What if I need birth control for more than 5 years?

Mirena must be removed after 5 years. Your healthcare provider can place a new Mirena during the same office visit if you choose to continue using Mirena.

What if I want to stop using Mirena?

Mirena is intended for long-term use but you can stop using Mirena at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Mirena is removed, so you should use another method of birth control if you do not want to become pregnant.

What if I change my mind about birth control and want to become pregnant in less than 5 years?

Your healthcare provider can remove Mirena at any time. You may become pregnant as soon as Mirena is removed. About 8 out of 10 women who want to become pregnant will become pregnant sometime in the first year after Mirena is removed.

How does Mirena work?

Mirena may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy.

Mirena can cause your menstrual bleeding to be less by thinning the lining of the uterus.

How well does Mirena work for contraception?

The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.

Mirena, an intrauterine device (IUD), is in the box at the top of the chart.

How well does Mirena work for heavy menstrual bleeding?

In the clinical trial performed in women with heavy menstrual bleeding and treated with Mirena, almost 9 out of 10 were treated successfully and their blood loss was reduced by more than half.

Who might use Mirena?

You might choose Mirena if you:

· Want long-term birth control that provides a low chance of getting pregnant (less than 1 in 100)

· Want birth control that works continuously for up to 5 years

· Want birth control that is reversible

· Want a birth control method that you do not need to take daily

· Have had at least one child

· Want treatment for heavy periods and are willing to use a birth control method that is placed in the uterus

· Want birth control that does not contain estrogen

Who should not use Mirena?

Do not use Mirena if you:

· Are or might be pregnant; Mirena cannot be used as an emergency contraceptive

· Have had a serious pelvic infection called pelvic inflammatory disease (PID) unless you have had a normal pregnancy after the infection went away

· Have an untreated pelvic infection now

· Have had a serious pelvic infection in the past 3 months after a pregnancy

· Can get infections easily. For example, if you have:

o Multiple sexual partners or your partner has multiple sexual partners

o Problems with your immune system

o Intravenous drug abuse.

· Have or suspect you might have cancer of the uterus or cervix

· Have bleeding from the vagina that has not been explained

· Have liver disease or liver tumor

· Have breast cancer or any other cancer that is sensitive to progestin (a female hormone), now or in the past

· Have an intrauterine device in your uterus already

· Have a condition of the uterus that changes the shape of the uterine cavity, such as large fibroid tumors

· Are allergic to levonorgestrel, silicone, polyethylene, silica, barium sulfate or iron oxide

Before having Mirena placed, tell your healthcare provider if you:

· Have had a heart attack

· Have had a stroke

· Were born with heart disease or have problems with your heart valves

· Have problems with blood clotting or take medicine to reduce clotting

· Have high blood pressure

· Recently had a baby or if you are breastfeeding

· Have severe migraine headaches.

How is Mirena placed?

Mirena is placed by your healthcare provider during an in-office visit.

First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution, and slide a slim plastic tube containing Mirena into your uterus. Your healthcare provider will then remove the plastic tube, and leave Mirena in your uterus. Your healthcare provider will cut the threads to the right length. Placement takes only a few minutes.

You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Mirena may not have been placed correctly. Your healthcare provider will examine you to see if Mirena needs to be removed or replaced.

Should I check that Mirena is in place?

Yes, you should check that Mirena is in proper position by feeling the removal threads. It is a good habit to do this once a month. Your healthcare provider should tell you how to check that Mirena is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Mirena may not be in the right position and may not prevent pregnancy. Use non-hormonal back-up birth control (such as condoms and spermicide) and ask your healthcare provider to check that Mirena is still in the right place.

How soon after placement of Mirena should I return to my healthcare provider?

Call your healthcare provider if you have any questions or concerns (see “When should I call my healthcare provider“). Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 6 weeks after Mirena is placed to make sure that Mirena is in the right position.

Can I use tampons with Mirena?

Tampons may be used with Mirena.

What if I become pregnant while using Mirena?

Call your healthcare provider right away if you think you are pregnant. If you get pregnant while using Mirena, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy.

Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death.

There are also risks if you get pregnant while using Mirena and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device (IUD). Because of this, your healthcare provider may try to remove Mirena, even though removing it may cause a miscarriage. If Mirena cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy.

If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection.

It is not known if Mirena can cause long-term effects on the fetus if it stays in place during a pregnancy.

How will Mirena change my periods?

For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. After you have used Mirena for a while, the number of bleeding and spotting days is likely to lessen. There is a small chance that your periods will stop altogether.

In some women with heavy bleeding, the total blood loss per cycle progressively decreases with continued use. The number of spotting and bleeding days may initially increase but then typically decreases in the months that follow.

Is it safe to breastfeed while using Mirena?

You may use Mirena when you are breastfeeding if more than six weeks have passed since you had your baby. If you are breastfeeding, Mirena is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported among women using progestin-only birth control pills. The risk of Mirena becoming attached to (embedded) or going through the wall of the uterus is increased if Mirena is inserted while you are breastfeeding.

Will Mirena interfere with sexual intercourse?

You and your partner should not feel Mirena during intercourse. Mirena is placed in the uterus, not in the vagina. Sometimes your partner feels the threads. If this occurs, talk with your healthcare provider.

What are the possible side effects of using Mirena?

Mirena can cause serious side effects including:

· Pelvic inflammatory disease (PID). Some IUD users get a serious pelvic infection called pelvic inflammatory disease. PID is usually sexually transmitted. You have a higher chance of getting PID if you or your partner have sex with other partners. PID can cause serious problems such as infertility, ectopic pregnancy or pelvic pain that does not go away. PID is usually treated with antibiotics. More serious cases of PID may require surgery. A hysterectomy (removal of the uterus) is sometimes needed. In rare cases, infections that start as PID can even cause death.

· Tell your healthcare provider right away if you have any of these signs of PID: long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal (stomach area) pain, painful sex, chills, or fever.

· Life-threatening infection. Life-threatening infection can occur within the first few days after Mirena is placed. Call your healthcare provider immediately if you develop severe pain or fever shortly after Mirena is placed.

· Perforation. Mirena may become attached to (embedded) or go through the wall of the uterus. This is called perforation. If this occurs, Mirena may no longer prevent pregnancy. If perforation occurs, Mirena may move outside the uterus and can cause internal scarring, infection, or damage to other organs, and you may need surgery to have Mirena removed. The risk of perforation is increased if Mirena is inserted while you are breastfeeding.

Common side effects of Mirena include:

· Pain, bleeding or dizziness during and after placement. If these symptoms do not stop 30 minutes after placement, Mirena may not have been placed correctly. Your healthcare provider will examine you to see if Mirena needs to be removed or replaced.

· Expulsion. Mirena may come out by itself. This is called expulsion. You may become pregnant if Mirena comes out. If you think that Mirena has come out, use a backup birth control method like condoms and spermicide and call your healthcare provider.

· Missed menstrual periods. About 2 out of 10 women stop having periods after 1 year of Mirena use. If you do not have a period for 6 weeks during Mirena use, call your healthcare provider. When Mirena is removed, your menstrual periods will come back.

· Changes in bleeding. You may have bleeding and spotting between menstrual periods, especially during the first 3 to 6 months. Sometimes the bleeding is heavier than usual at first. However, the bleeding usually becomes lighter than usual and may be irregular. Call your healthcare provider if the bleeding remains heavier than usual or increases after it has been light for a while.

· Cysts on the ovary. About 12 out of 100 women using Mirena develop a cyst on the ovary. These cysts usually disappear on their own in a month or two. However, cysts can cause pain and sometimes cysts will need surgery.

This is not a complete list of possible side effects with Mirena. For more information, ask your healthcare provider.

Call your doctor for medical advice about side effects. You may report side effects to the manufacturer at 1-888-842-2937, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

After Mirena has been placed, when should I call my healthcare provider?

Call your healthcare provider if you have any concerns about Mirena. Be sure to call if you:

· Think you are pregnant

· Have pelvic pain or pain during sex

· Have unusual vaginal discharge or genital sores

· Have unexplained fever, flu-like symptoms or chills

· Might be exposed to sexually transmitted infections (STIs)

· Cannot feel Mirena's threads

· Develop very severe or migraine headaches

· Have yellowing of the skin or whites of the eyes. These may be signs of liver problems.

· Have had a stroke or heart attack

· Or your partner becomes HIV positive

· Have severe vaginal bleeding or bleeding that lasts a long time