Synarel

中枢性性早熟（子宫内膜异位症，SEE REVERSE SIDE ）

医师标签

同步描述

Synarel（醋酸那法瑞林）鼻用溶液旨在以喷雾剂的形式施用于鼻粘膜。那法瑞林乙酸盐，Synarel鼻用溶液中的活性成分，是具有化学名称的十肽：5-氧代-1- -prolyl-大号-histidyl-大号-tryptophyl-大号-seryl-大号-tyrosyl -3-（2-萘基） -D-丙氨酰基-L-亮氨酰基-L-精氨酰基-L-脯氨酰-甘氨酰胺乙酸酯。醋酸那法林是天然存在的促性腺激素释放激素（GnRH）的合成类似物。

醋酸萘法林具有以下化学结构：

∙x CH 3 COOH∙y H 2 O（1 x x 2; 2 x 8）

Synarel鼻用溶液在苯扎氯铵，冰醋酸，氢氧化钠或盐酸（调节pH），山梨糖醇和纯净水的溶液中包含乙酸萘法林（2 mg / mL，含量以萘法林碱表示）。

在为Synarel灌注泵单元后，每次启动该单元都会释放大约100 µL的喷雾剂，其中包含约200 µg萘萘酚碱。一个喷雾瓶的内装物可提供至少60次喷雾。

Synarel-临床药理学

醋酸那法林是促性腺激素释放激素（GnRH）的有效激动剂类似物。在开始给药时，那法瑞林刺激垂体促性腺激素LH和FSH的释放，导致性腺类固醇生成的暂时增加。重复给药消除了对垂体的刺激作用。每天两次给药导致性腺类固醇的分泌减少约4周。因此，依赖性腺类固醇维持其功能的组织和功能变得静止。

在儿童中，鼻内给药后醋酸纳法瑞林被迅速吸收到体循环中。在10至45分钟之间达到最大血清浓度（通过RIA测量）。单剂量400 µg碱后，观察到的峰浓度为2.2 ng / mL，而单剂量600 µg碱后，观察到的峰浓度为6.6 ng / mL。鼻内给予400 µg剂量后，那法瑞林的平均血清半衰期约为2.5小时。尚不知道并且无法预测纳法瑞林在600 µg以上剂量的儿童中的药代动力学。

在成年女性中，鼻内给药后醋酸纳法瑞林被迅速吸收到体循环中。在10至40分钟之间达到最大血清浓度（通过RIA测量）。单次剂量为200 µg碱后，观察到的平均峰浓度为0.6 ng / mL（范围为0.2到1.4 ng / mL），而单次剂量为400 µg碱后，观察到的平均峰浓度为1.8 ng / mL（范围0.5至5.3 ng / mL）。 400 µg剂量的生物利用度平均为2.8％（范围为1.2至5.6％）。鼻内给药后那法瑞林的平均血清半衰期约为3小时。在4℃下约80％的醋酸萘法林与血浆蛋白结合。在18位健康女性中，每天两次鼻内给药200或400 µg Synarel，共22天，并未导致药物的大量积聚。根据第15天和第22天的平均C min水平，两个剂量水平似乎存在剂量比例关系。

男性皮下注射14 C-那法瑞林醋酸盐后，尿液中的剂量恢复到44-55％，粪便中的剂量恢复到18.5-44.2％。大约3％的给药剂量在尿中表现为不变的那法瑞林。代谢物的14 C血清半衰期约为85.5小时。纳法瑞林的六种代谢物已被鉴定，其中主要代谢物是Tyr-D（2）-Nal-Leu-Arg-Pro-Gly-NH 2 （5-10）。尚没有确定肝，肾功能不全患者的代谢产物活性，纳法瑞林经鼻粘膜的代谢以及该药的药代动力学。

鼻炎，即鼻充血，对Synarel的全身生物利用度似乎没有显着影响。但是，如果在用Synarel治疗期间必须使用鼻充血剂治疗鼻炎，则应在服用Synarel至少2小时后才使用充血剂。

当以推荐剂量在中枢性性早熟（CPP）的女孩和男孩中定期使用时，Synarel可将LH和性类固醇激素水平抑制到青春期前水平，影响相应的继发性性发育停滞，并减缓线性生长和骨骼成熟。在某些情况下，通常在治疗开始后的6周内，可能会发生最初的雌激素戒断性出血。此后，月经应该停止。

在临床研究中，LH对GnRH刺激的峰值反应在治疗后1个月内从青春期反应降低到青春期前反应（<15 mlU / mL）。

在CPP儿童中通常青春期的线性生长速度在治疗的第一年内在大多数儿童中降低到5至6 cm /年或更低的值。患有CPP的儿童通常比同龄儿童高。在Synarel治疗的第二年或第三年中，大多数儿童的年龄年龄高度都接近正常。 CPP患儿的骨骼成熟率（骨龄速度-骨龄变化除以年龄变化）通常是异常的（大于1）。在大多数儿童中，治疗的第一年骨龄速度接近正常（1）。通常在治疗的第二年或第三年，这会导致骨龄和时间年龄之间的差距缩小。平均预测成人身高增加。

在临床试验中，82％的女孩的乳房发育被阻止或消退，而100％的男孩的生殖器发育被阻止或消退。由于阴毛的生长主要受肾上腺雄激素的控制，而肾上腺素不受萘法林的影响，因此只有54％的女孩和男孩的阴毛生长被阻止或消退。

事实证明，在所有可进行一年治疗后随访的CPP儿童中，都能逆转Synarel的抑制作用（n = 69）。该证明包括月经的出现或复发，青春期促性腺激素和性腺性类固醇水平的恢复和/或继发性发育的进展。到目前为止，从接受过治疗以恢复青春期的男孩身上获得的两个射精标本中的精液分析是正常的。怀孕尚未证明有生育能力，长期使用该药物对生育能力的影响尚不清楚。

中央早搏的适应症和用途

（关于子宫内膜异位症，请参见背面）

Synarel适用于治疗男女儿童中枢性早熟（CPP） （促性腺激素依赖性早熟）。

当女孩在8岁以下或男孩在9岁以下发生继发性特征的过早发展时，怀疑患有中枢性早熟（CPP） ，并伴有骨龄和/或成年贫困的显着进展。高度预测。应通过青春期性腺类固醇水平和对自然GnRH刺激的青春期LH反应来确认诊断。女孩的盆腔超声检查通常显示子宫和卵巢增大，后者通常具有多个囊性结构。建议使用磁共振成像或脑部CT扫描来检测下丘脑或垂体肿瘤，或与颅内压升高相关的解剖学变化。性早熟的其他原因，例如先天性肾上腺皮质增生，睾丸中毒，睾丸肿瘤和/或其他自主性女性化或男性化疾病，必须通过适当的临床荷尔蒙和诊断性影像学检查排除。

禁忌症

1.对GnRH，GnRH激动剂类似物或Synarel中的任何赋形剂过敏；

2.未经诊断的异常阴道出血；

3.用于怀孕或在服药期间可能怀孕的妇女中使用。对孕妇服用Synarel可能会造成胎儿伤害。在器官发生期间，在使用Synarel后，在大鼠中观察到了重大胎儿异常，但在小鼠或兔子中未观察到。大鼠的胎儿死亡率与剂量有关，胎儿体重减少[见妊娠] 。对大鼠胎儿死亡率的影响是该药物引起的激素水平改变的预期结果。如果该药物是在怀孕期间使用的，或者患者在服用该药物时怀孕，则应告知她对胎儿的潜在危害；

4.用于母乳喂养的妇女[参见哺乳母亲]。

警告事项

在开始治疗之前，必须先确定中枢性早熟（CPP）的诊断。需要定期监测CPP患者以评估患者反应和依从性。在治疗的最初6至8周内，这一点尤其重要，以确保垂体-性腺功能的抑制迅速。测试可能包括LH对GnRH刺激和循环性腺性类固醇水平的反应。生长速度和骨龄速度的评估应在治疗开始后的3到6个月内开始。

一些患者可能未通过临床和/或生化参数显示垂体-性腺轴的抑制。这可能是由于缺乏对推荐治疗方案的依从性，并且可以通过建议由护理人员进行给药来纠正。如果排除顺应性问题，应重新考虑促性腺激素独立性早熟的可能性，并进行适当的检查。如果排除了依从性问题，并且如果不存在促性腺激素依赖性的性早熟，则Synarel的剂量可以增加到1800 µg /天，作为600 µg tid。

据报道服用GnRH激动剂的患者发生精神病事件。此类药物的上市后报告包括情绪不佳的症状，例如哭泣，烦躁，不耐烦，愤怒和攻击性。监测Synarel治疗期间精神症状的发展或恶化。

在接受GnRH激动剂的患者中发现了惊厥的上市后报告。这些患者包括有癫痫发作，癫痫，脑血管疾病，中枢神经系统异常或肿瘤病史的患者，以及服用与抽搐相关的药物（如安非他酮和SSRIs）的患者。在没有上述任何病症的情况下，也有惊厥的报道。

预防措施

一般

与刺激促性腺激素释放或诱导排卵的其他药物一样，据报道，在患有子宫内膜异位的成年女性中，卵巢囊肿在Synarel治疗的头两个月发生。这些事件中有许多但并非全部发生在多囊卵巢疾病女性中。这些囊性肿大通常可在治疗约四到六周后自发消退，但在某些情况下可能需要停止药物和/或手术干预。此类事件在儿童中的相关性（如果有的话）是未知的。

给患者，患者父母或监护人的信息

产品随附患者手册。患者及其看护者应了解以下信息：

1.月经的出现或复发，青春期促性腺激素和性腺激素的水平和/或继发性发育的进展证明了那法瑞林抑制作用的可逆性。到目前为止，两个男孩的精液分析结果正常，这些男孩已经接受了恢复青春期的治疗。怀孕尚未证明有生育能力，长期使用该药物对生育能力的影响尚不清楚。

2.应当对患者及其护理人员进行充分的咨询，以确保其完全合规；每日不规则剂量或剂量不完全可能会刺激垂体-性腺轴。

3.通知父母在接受GnRH激动剂的患者中发现了惊厥的报告。有癫痫发作，癫痫，脑血管疾病，中枢神经系统异常或肿瘤病史的患者，以及与惊厥相关的同时用药的患者，患病风险可能增加[见警告]。

4.告知护理人员，在接受GnRH激动剂的患者中发现了惊厥的报告。有癫痫发作，癫痫，脑血管疾病，中枢神经系统异常或肿瘤病史的患者，以及与惊厥相关的同时用药的患者，患病风险可能增加[见警告]。

5.在用Synarel治疗的第一个月中，可能会出现一些青春期迹象，例如阴道出血或乳房增大。这是该药物的预期初始作用。这种变化应在第一个月后尽快解决。如果在治疗的头两个月内未出现这种解决方法，则可能是由于缺乏依从性或存在促性腺激素非依赖性的性早熟。如果绝对排除了这两种可能性，则Synarel的剂量可以增加到1800 µg /天，作为600 µg tid。

6.并发性鼻炎的患者应咨询医生以使用局部鼻充血剂。如果在用Synarel治疗期间需要使用局部鼻腔充血剂，则在使用Synarel给药后至少2小时才应使用充血剂。

如果可能，应避免在Synarel给药期间或给药后立即打喷嚏，因为这可能会损害药物吸收。

药物相互作用

Synarel尚未进行基于药代动力学的药物相互作用研究。但是，由于乙酸那法瑞林是主要被肽酶而不是细胞色素P-450酶降解的肽，并且该药物在4°C下仅与血浆蛋白结合约80％，因此预计不会发生药物相互作用。

致癌，诱变，生育力受损

纳法林的致癌性研究是在大鼠（24个月）以最高100 µg / kg / day的剂量进行的，小鼠（18个月）以500μg/ kg / day的剂量进行的，使用的是肌肉注射剂量（分别为110倍和560倍）。分别建议的最大人类鼻内剂量）。人剂量的这些倍数基于两种给药途径中药物的相对生物利用度。如与其他GnRH激动剂所见，将纳法瑞林乙酸酯长期以高剂量给予实验室啮齿动物会引起内分泌器官的增生反应（增生和/或瘤形成）。在24个月时，大剂量雌性大鼠脑垂体瘤（腺瘤/癌）的发生率增加，雄性大鼠中与剂量有关的剂量增加。两组的胰岛细胞腺瘤以及治疗组的睾丸和卵巢良性肿瘤均增加。在治疗的雌性大鼠中，良性肾上腺髓质肿瘤的剂量相关增加。在小鼠中，雄性哈德氏腺瘤与剂量有关，而大剂量雌性脑垂体腺瘤与剂量有关。没有观察到这些肿瘤的转移。已知啮齿动物的致瘤性对激素刺激特别敏感。

使用细菌，酵母和哺乳动物系统，用乙酸萘法林进行致突变性研究。这些研究没有提供诱变潜力的证据。

在雄性和雌性大鼠中的生殖研究表明，连续给药长达6个月后停止药物治疗时，生育抑制的完全可逆性。尚未研究青春期前大鼠对成熟动物随后的生殖性能的影响。

怀孕

请参阅禁忌症。在器官发生期间，大鼠以0.4、1.6和6.4 µg / kg /天的剂量向大鼠肌内Synarel给药（基于两种给药方式的相对生物利用度，约为人推荐最大鼻内剂量的0.5、2和7倍） 。在最高剂量下，有4/80胎儿的主要胎儿异常现象有所增加。在大鼠中以相同剂量，分别以最高600 µg / kg /天和0.18 µg / kg /天的剂量分别在小鼠和兔子中进行的一项类似的重复研究未能证明在此期间给药后胎儿异常的增加器官发生。在大鼠和兔子中，剂量最高时，胎儿死亡率与剂量相关，而胎儿体重下降。

护理母亲

不知道Synarel是否从人乳中排出。由于许多药物会从人乳中排出，并且由于尚未确定Synarel对泌乳和/或母乳喂养孩子的影响，因此哺乳期的母亲不应使用Synarel。

不良反应

在155名儿科患者的临床试验中，有2.6％的患者报告表明存在药物敏感性症状，例如呼吸急促，胸痛，荨麻疹，皮疹和瘙痒。

在这155位平均接受41个月且长达80个月（6.7年）的患者中，最常报告的不良事件（> 3％的患者）主要是由于治疗的前6周内发生的发作萘法林对垂体-性腺轴的短暂刺激作用：

痤疮（10％）

短暂性乳房增大（8％）

阴道出血（8％）

情绪不稳定（6％） [请参阅警告]

阴毛短暂增加（5％）

体臭（4％）

皮脂溢（3％）

潮热常见于接受子宫内膜异位症治疗的成年女性中，仅在3％的受治疗儿童中发生并且是短暂的。其他被认为与药物有关的不良事件，并在超过3％的患者中发生，包括鼻炎（5％）和白色或褐色的白带（3％）。由于不良事件，约有3％的患者退出了临床试验。

一名患有先天性肾上腺皮质增生并在8个月前停止治疗以恢复青春期的男性患者中，在左睾丸中发现了肾上腺休息肿瘤。与Synarel的关系不太可能。

长期在那法瑞林治疗期间以及在治疗后期间，通过磁共振成像（MRI）或计算机辅助断层扫描（CT）对儿童的垂体进行定期检查，偶尔会发现垂体的形状和大小发生变化。这些变化包括垂体的不对称和增大，并且怀疑有少数儿童患有垂体微腺瘤。这些发现与Synarel的关系尚不清楚。

上市后

垂体中风：在上市后的监测中，已报告了施用促性腺激素释放激素激动剂后发生的垂体中风罕见病例（一种由垂体梗死继发的临床综合征）。在大多数这些病例中，诊断为垂体腺瘤，大多数垂体中风病例在首次给药后2周内发生，有些在第一小时内发生。在这些情况下，垂体中风表现为突然的头痛，呕吐，视觉改变，眼肌麻痹，精神状态改变，有时甚至是心血管衰竭。需要立即就医。

精神疾病不良事件： GnRH激动剂已观察到情绪不稳，如哭泣，烦躁，不耐烦，愤怒和攻击性[请参阅警告] ； GnRH激动剂治疗中枢性性早熟儿童的抑郁症，包括罕见的自杀意念和尝试报道。这些患者中有很多（但不是全部）有精神病史或其他合并症，抑郁风险增加。

中枢/周围神经不良事件：惊厥。

过量

在实验动物中，单次皮下给药剂量是推荐人剂量的60倍（以µg / kg为基础，未根据生物利用度进行调整），不会产生不良影响。目前，尚无过量服用GnRH类似物后产生不良反应的临床证据。

根据猴子的研究，口服Synarel不会被吸收。

Synarel剂量和给药

对于中枢性性早熟（CPP），Synarel的建议每日剂量为1600 µg。如果不能以每天1600 µg的剂量获得足够的抑制作用，则每天的剂量可以增加到1800 µg。

1600克的剂量是通过在早晨向每个鼻孔喷两次（400微克）（4喷），在晚上向每个鼻孔喷两次（4喷），每天总共8喷。每天3次向交替的鼻孔中喷3次（600 µg），可达到1800 µg的剂量，每天总共9次。病人的头部应稍微向后倾斜，两次喷雾之间应间隔30秒。

如果患者对处方疗法的耐受性良好，则应继续使用Synarel治疗CPP，直到需要恢复青春期。

鼻炎，即鼻充血，对Synarel的全身生物利用度似乎没有显着影响。但是，如果在用Synarel治疗期间必须使用鼻充血剂治疗鼻炎，则应在服用Synarel至少2小时后才使用充血剂。

如果可能，应避免在Synarel给药期间或给药后立即打喷嚏，因为这可能会损害药物吸收。

一瓶Synarel的日剂量为1600 µg /天，提供约7天的剂量（约56次喷雾）。如果每日剂量增加，请增加对患者的供应，以确保在治疗期间不间断的治疗。

如何提供Synarel

每个0.5盎司的瓶子（NDC 0025-0166-08）包含8 mL Synarel（醋酸那法林）鼻用溶液2 mg / mL（以那法林碱为基础），并配有计量喷雾泵，每次喷雾可提供200 µg萘法林。还包括防尘罩和患者说明传单。

直立存放于25°C（77°F）；允许在15–30°C（59–86°F）的范围内偏移[请参阅USP控制的室温]。避光。

LAB-1048-2.0
2017年12月

Synarel®
（醋酸萘法林）
鼻溶液

子宫内膜异位症（FOR中枢性性早熟，SEE REVERSE SIDE ）

医师标签

同步描述

Synarel（醋酸那法瑞林）鼻用溶液旨在以喷雾剂的形式施用于鼻粘膜。那法瑞林乙酸盐，Synarel鼻用溶液中的活性成分，是具有化学名称的十肽：5-氧代-1- -prolyl-大号-histidyl-大号-tryptophyl-大号-seryl-大号-tyrosyl -3-（2-萘基） -D-丙氨酰基-L-亮氨酰基-L-精氨酰基-L-脯氨酰-甘氨酰胺乙酸酯。醋酸那法林是天然存在的促性腺激素释放激素（GnRH）的合成类似物。

醋酸萘法林具有以下化学结构：

∙x CH 3 COOH∙y H 2 O（1 x x 2; 2 x 8）

Synarel鼻用溶液在苯扎氯铵，冰醋酸，氢氧化钠或盐酸（调节pH），山梨糖醇和纯净水的溶液中包含乙酸萘法林（2 mg / mL，含量以萘法林碱表示）。

在为Synarel灌注泵单元后，每次启动该单元都会释放大约100 µL的喷雾剂，其中包含约200 µg萘萘酚碱。一个喷雾瓶的内装物可提供至少60次喷雾。

Synarel-临床药理学

醋酸那法林是促性腺激素释放激素（GnRH）的有效激动剂类似物。在给药开始时，那法瑞林刺激垂体促性腺激素LH和FSH释放，导致卵巢类固醇生成暂时增加。重复给药消除了对垂体的刺激作用。每天两次给药导致性腺类固醇的分泌减少约4周。因此，依赖性腺类固醇维持其功能的组织和功能变得静止。

鼻内给药后乙酸纳法瑞林被迅速吸收到全身循环中。在10至40分钟之间达到最大血清浓度（通过RIA测量）。单次剂量为200 µg碱后，观察到的平均峰浓度为0.6 ng / mL（范围为0.2到1.4 ng / mL），而单次剂量为400 µg碱后，观察到的平均峰浓度为1.8 ng / mL（范围0.5至5.3 ng / mL）。 400 µg剂量的生物利用度平均为2.8％（范围为1.2至5.6％）。鼻内给药后那法瑞林的平均血清半衰期约为3小时。在4°C时，约80％的醋酸萘法林与血浆蛋白结合。在18位健康女性中，每天两次鼻内给药200或400 µg Synarel，共22天，并未导致药物的大量积聚。根据第15天和第22天的平均C min水平，两个剂量水平似乎存在剂量比例关系。

男性皮下注射14 C-那法瑞林醋酸盐后，尿液中的剂量恢复到44-55％，粪便中的剂量恢复到18.5-44.2％。大约3％的给药剂量在尿中表现为不变的那法瑞林。代谢物的14 C血清半衰期约为85.5小时。纳法瑞林的六种代谢物已被鉴定，其中主要代谢物是Tyr-D（2）-Nal-Leu-Arg-Pro-Gly-NH 2 （5-10）。尚没有确定肝，肾功能不全患者的代谢产物活性，纳法瑞林经鼻粘膜的代谢以及该药的药代动力学。

鼻炎，即鼻充血，对Synarel的全身生物利用度似乎没有明显影响。但是，如果在Synarel的治疗过程中需要使用鼻充血剂治疗鼻炎，则应在服用Synarel至少2小时后才使用充血剂。

在对照临床研究中，在缓解子宫内膜异位症（盆腔疼痛，痛经和性交困难）的临床症状以及减轻子宫内膜异位症（骨盆痛，痛经和性交困难）方面，以400和800 µg /天的剂量持续6个月的Synarel与达那唑800 mg /天相当。通过腹腔镜检查确定子宫内膜植入物的大小。目前尚不知道子宫内膜异位病变减少的临床意义，此外，腹腔镜检查子宫内膜异位的分期不一定与症状的严重程度相关。

在一项单独的对照临床试验中，鼻内Synarel（醋酸萘法瑞林）每天400 µg的剂量在临床上可与肌内亮丙瑞德仓库（每月3.75 mg）用于治疗症状（痛经，痛经和骨盆痛）相媲美。与子宫内膜异位症有关。

Synarel每天400 µg分别在60、90和120天后分别引起大约65％，80％和90％的患者闭经。在治疗后的第一，第二和第三个月中，未怀孕的患者分别恢复了正常的月经周期的4％，82％和100％。

在治疗结束时，接受Synarel（400微克/天）的患者中有60％没有症状，32％的症状较轻，7％的症状为中度，1％的症状为重度。在治疗结束后症状完全缓解的60％患者中，有17％在停药后6个月出现中度症状，33％出现轻度症状，50％保持无症状，并且没有患者出现严重症状。

在使用Synarel的前两个月中，一些女性会经历持续时间和强度不同的阴道出血。这种出血很可能代表雌激素戒断出血，并且有望自发停止。如果阴道流血继续，应考虑不遵守给药方案的可能性。如果患者认真遵守该方案，则应考虑每天两次将剂量增加至400 µg。

没有证据表明使用Synarel可提高妊娠率或对妊娠率产生不利影响。

子宫内膜异位症的适应症和用途

（对于中枢性性早熟，请参见背面）

Synarel适用于子宫内膜异位症的治疗，包括缓解疼痛和减少子宫内膜异位病灶。 Synarel处理子宫内膜异位的经验仅限于18岁以上且治疗6个月以上的女性。

禁忌症

1.对GnRH，GnRH激动剂类似物或Synarel中的任何赋形剂过敏；
2.未经诊断的异常阴道出血；
3.用于怀孕或在服药期间可能怀孕的妇女中使用。对孕妇服用Synarel可能会造成胎儿伤害。在器官发生期间，在使用Synarel后，在大鼠中观察到了重大胎儿异常，但在小鼠或兔子中未观察到。大鼠的胎儿死亡率与剂量有关，胎儿的体重减少[见妊娠] 。对大鼠胎儿死亡率的影响是该药物引起的激素水平改变的预期结果。如果在怀孕期间使用该药物，或者患者在服用该药物时怀孕，则应告知她对胎儿的潜在危害；
4.使用妇女谁是哺乳[见哺乳期妇女。

警告事项

临床上尚未确定孕妇可安全使用醋酸那法瑞林。在开始使用Synarel治疗之前，必须排除妊娠。

当以推荐剂量定期使用时，Synarel通常会抑制排卵并停止月经。但是，服用Synarel不能保证避孕效果，特别是如果患者错过连续剂量的话。因此，患者应使用非激素避孕方法。如果患者认为自己可能怀孕，应该建议他们去看医生。如果患者在治疗期间怀孕，则必须停用该药物，并且必须告知患者胎儿的潜在危险。

预防措施

一般

与其他刺激促性腺激素释放或诱导排卵的药物一样，据报道，在Synarel治疗的头两个月中，卵巢囊肿就发生了。这些事件中有很多（但不是全部）发生在多囊卵巢疾病患者中。这些囊性肿大通常可在治疗约四到六周后自发消退，但在某些情况下可能需要停止药物和/或手术干预。

给患者的信息

产品随附患者手册。患者应注意以下信息：

1.由于应以有效剂量的Synarel停止月经，如果常规月经持续，患者应通知医生。阴道斑点，出血或月经的原因可能与治疗方案不符，或者可能需要更高剂量的药物才能达到闭经。应询问患者其依从性。如果她谨慎而顺从，并且月经持续到第二个月，则应考虑将Synarel的剂量加倍。如果患者错过了几次剂量，应告知她按处方定期服用Synarel的重要性。

2.如果孕妇，母乳喂养，未经诊断的异常阴道出血或对Synarel中的任何成分过敏，则患者不应使用Synarel。

3.尚未在临床上确定在孕妇中安全使用该药物。 Therefore, a nonhormonal method of contraception should be used during treatment. Patients should be advised that if they miss successive doses of Synarel, breakthrough bleeding or ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.

4. Those adverse events occurring most frequently in clinical studies with Synarel are associated with hypoestrogenism; the most frequently reported are hot flashes, headaches, emotional lability, decreased libido, vaginal dryness, acne, myalgia, and reduction in breast size. Estrogen levels returned to normal after treatment was discontinued. Nasal irritation occurred in about 10% of all patients who used intranasal nafarelin.

5. The induced hypoestrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible. During one six-month treatment period, this bone loss should not be important. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, therapy with Synarel may pose an additional risk. In these patients the risks and benefits must be weighed carefully before therapy with Synarel is instituted. Repeated courses of treatment with gonadotropin-releasing hormone analogs are not advisable in patients with major risk factors for loss of bone mineral content.

6. Patients with intercurrent rhinitis should consult their physician for the use of a topical nasal decongestant. If the use of a topical nasal decongestant is required during treatment with Synarel, the decongestant should not be used until at least 2 hours following dosing with Synarel.

Sneezing during or immediately after dosing with Synarel should be avoided, if possible, since this may impair drug absorption.

7. Retreatment cannot be recommended since safety data beyond 6 months are not available.

药物相互作用

No pharmacokinetic-based drug-drug interaction studies have been conducted with Synarel. However, because nafarelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound to plasma proteins at 4°C, drug interactions would not be expected to occur.

Drug/Laboratory Test Interactions

Administration of Synarel in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 8 weeks after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to 4 to 8 weeks after discontinuation of therapy with Synarel may be misleading.

致癌，诱变，生育力受损

Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560 times the maximum recommended human intranasal dose, respectively). These multiples of the human dose are based on the relative bioavailability of the drug by the two routes of administration. As seen with other GnRH agonists, nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors in the treated groups. There was a dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was a dose-related increase in Harderian gland tumors in males and an increase in pituitary adenomas in high-dose females. No metastases of these tumors were observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal stimulation.

Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and mammalian systems. These studies provided no evidence of mutagenic potential.

Reproduction studies in male and female rats have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated.

怀孕

See Contraindications . Intramuscular Synarel was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day (about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on the relative bioavailability by the two routes of administration). An increase in major fetal abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and 0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was a dose-related increase in fetal mortality and a decrease in fetal weight with the highest dose.

护理母亲

It is not known whether Synarel is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Synarel on lactation and/or the breastfed child have not been determined, Synarel should not be used by nursing mothers.

儿科用

Safety and effectiveness of Synarel for endometriosis in patients younger than 18 years have not been established.

不良反应

临床研究

In formal clinical trials of 1509 healthy adult patients, symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash and pruritus occurred in 3 patients (approximately 0.2%).

As would be expected with a drug which lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.

In controlled studies comparing Synarel (400 µg/day) and danazol (600 or 800 mg/day), adverse reactions most frequently reported and thought to be drug-related are shown in the figure below:

In addition, less than 1% of patients experienced paresthesia, palpitations, chloasma, maculopapular rash, eye pain, asthenia, lactation, breast engorgement, and arthralgia.

Changes in Bone Density

After six months of treatment with Synarel, vertebral trabecular bone density and total vertebral bone mass, measured by quantitative computed tomography (QCT), decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment levels. There was partial recovery of bone density in the post-treatment period; the average trabecular bone density and total bone mass were 4.9% and 3.3% less than the pretreatment levels, respectively. Total vertebral bone mass, measured by dual photon absorptiometry (DPA), decreased by a mean of 5.9% at the end of treatment.

After six months treatment with Synarel, bone mass as measured by dual x-ray bone densitometry (DEXA), decreased 3.2%. Mean total vertebral mass, re-examined by DEXA six months after completion of treatment, was 1.4% below pretreatment. There was little, if any, decrease in the mineral content in compact bone of the distal radius and second metacarpal. Use of Synarel for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Changes in Laboratory Values During Treatment

During clinical trials with Synarel, regular laboratory monitoring revealed that SGOT and SGPT levels were more than twice the upper limit of normal in only one patient each. There was no other clinical or laboratory evidence of abnormal liver function and levels returned to normal in both patients after treatment was stopped.

At enrollment, 9% of the patients in the group taking Synarel 400 µg/day and 2% of the patients in the danazol group had total cholesterol values above 250 mg/dL. These patients also had cholesterol values above 250 mg/dL at the end of treatment.

Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in the group treated with Synarel and 18% in the danazol group, had post-treatment values above 250 mg/dL.

The mean (± SEM) pretreatment values for total cholesterol from all patients were 191.8 (4.3) mg/dL in the group treated with Synarel and 193.1 (4.6) mg/dL in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 204.5 (4.8) mg/dL in the group treated with Synarel and 207.7 (5.1) mg/dL in the danazol group. These increases from the pretreatment values were statistically significant (p<0.05) in both groups.

Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients who received Synarel and in 7% of the patients who received danazol.

At the end of treatment, no patients receiving Synarel had abnormally low HDL cholesterol fractions (less than 30 mg/dL) compared with 43% of patients receiving danazol. None of the patients receiving Synarel had abnormally high LDL cholesterol fractions (greater than 190 mg/dL) compared with 15% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving Synarel, but there was approximately a 2-fold increase in the LDL/HDL ratio in patients receiving danazol.

In comparative studies, the following changes were seen in approximately 10% to 15% of patients. Treatment with Synarel was associated with elevations of plasma phosphorus and eosinophil counts, and decreases in serum calcium and WBC counts. Danazol therapy was associated with an increase of hematocrit and WBC.

Post-Marketing

Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Cardiovascular adverse events: Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.

Central/peripheral nervous adverse events: Convulsion.

Hepatic adverse events: Rarely reported serious liver injury.

Reproductive system adverse events: Cases of ovarian hyperstimulation syndrome have been reported with Synarel monotherapy when used for Assisted Reproductive Technology which is not an approved indication.

过量

In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs.

Based on studies in monkeys, Synarel is not absorbed after oral administration.

Synarel Dosage and Administration

For the management of endometriosis, the recommended daily dose of Synarel is 400 µg. This is achieved by one spray (200 µg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle.

In an occasional patient, the 400 µg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of Synarel may be increased to 800 µg daily. The 800 µg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening.

The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with Synarel is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.

There appeared to be no significant effect of rhinitis, ie, nasal congestion, on the systemic bioavailability of Synarel; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with Synarel, the decongestant should not be used until at least 2 hours following dosing with Synarel.

Sneezing during or immediately after dosing with Synarel should be avoided, if possible, since this may impair drug absorption.

At 400 µg/day, a bottle of Synarel provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy.

How is Synarel Supplied

Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL Synarel (nafarelin acetate) Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient instructions are also included.

Store upright at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].避光。

仅Rx

LAB-0173-10.0
December 2017

Synarel
nafarelin acetate
鼻喷雾剂

Patient Instructions for Use

Introduction

Your doctor has prescribed Synarel Nasal Solution to treat your symptoms of endometriosis. This pamphlet has two purposes:

1.）

to review information your doctor has given you about Synarel;和

2.）

to give you information about how to use Synarel properly.

Please read this pamphlet carefully. If you still have questions after reading it or if you have questions at any time during your treatment with Synarel, be sure to check with your doctor.

Synarel is used to relieve the symptoms of endometriosis. The lining of the uterus is called the endometrium, and part of it is shed during menses. In endometriosis, endometrial tissue is also found outside the uterus and, like normal endometrial tissue, can bleed during a menstrual cycle. It is, in part, this monthly activity that causes you to have symptoms during your cycle. Most often, this out-of-place endometrial tissue is found around the uterus, ovaries, the intestine or other organs in the pelvis. Although some women with endometriosis have no symptoms, many have problems such as severe menstrual cramps, pain during sexual intercourse, low back pain, and painful bowel movements.

Endometrial tissue is affected by the body's hormones, especially estrogen, which is made by the ovaries. When estrogen levels are low, endometrial tissue shrinks (perhaps even disappears), and symptoms of endometriosis ease. Synarel temporarily reduces estrogen in the body and temporarily relieves the symptoms of endometriosis.

Important Information about Synarel

1. You should not use Synarel if
   • you are pregnant.
   • you are breast feeding.
   • you have abnormal vaginal bleeding that has not been checked into by your doctor.
   • you are allergic to any of the ingredients of Synarel (nafarelin acetate, benzalkonium chloride, acetic acid, sodium hydroxide, hydrochloric acid, sorbitol, purified water).
2. Synarel is a prescription medicine that should be used according to your doctor's directions. Synarel comes as a special nasal spray that gives a measured amount of medicine. To be effective, Synarel must be used every day, twice a day, for the whole treatment period.
3. It is important to use a non-hormonal method of contraception (such as diaphragm with contraceptive jelly, IUD, condoms) while taking Synarel. You should not use birth control pills while taking Synarel.
4. If you miss 1 or more doses of Synarel, vaginal bleeding (often called breakthrough bleeding) may occur. If you miss successive doses of Synarel and have not been using contraception as described above, release of an egg from the ovary (ovulation) may occur, with the possibility of pregnancy. Under these circumstances you must see your physician to make sure you are not pregnant. If you should become pregnant while using Synarel, you must discuss the possible risks to the fetus and the choices available to you with your physician.
5. Because Synarel works by temporarily reducing the body's production of estrogen, a female hormone produced by the ovary, you may have some of the same changes that normally occur at the time of menopause, when the body's production of estrogen naturally decreases. For the first two months after you start using Synarel, you may experience some irregular vaginal spotting or bleeding. The duration and intensity of this bleeding may vary; it may be similar to your usual menstruation, or it may be lighter or heavier. The duration may also vary from brief to prolonged. In any case, you can expect this bleeding to stop by itself. After the first two months of treatment with Synarel, you can expect a decrease in menstrual flow, and your periods may stop altogether. However, if you miss one or more doses of Synarel, you may continue to experience vaginal bleeding. If you continue to experience normal menstrual cycles after two months use of Synarel, you should see your doctor about the continued periods. Other changes due to decreased estrogen include hot flashes, vaginal dryness, headaches, mood changes, and decreased interest in sex. Most of these changes are caused by low estrogen levels and may occur during treatment with Synarel. Some patients may also experience acne, muscle pain, reduced breast size, and irritation of the tissues inside the nose. These symptoms should disappear after you stop taking the drug.
6. When you take Synarel, your estrogen levels will be low. Low estrogen levels can result in a small loss of mineral from bone, some of which may not be reversible. During one six-month treatment period, this small loss of mineral from bone should not be important.
   There are certain conditions that may increase the possibility of the thinning of your bones when you take a drug such as Synarel. They are:
   • excessive use of alcohol;
   • 抽烟;
   • family history of osteoporosis (thinning of the bones with fractures);
   • taking other medications that can cause thinning of the bones.
   You should discuss the possibility of osteoporosis or thinning of the bones with your physician before starting Synarel. You should also be aware that repeat treatments are not recommended since they may put you at greater risk of bone thinning, particularly if you have the above conditions.
7. During studies, menstruation usually resumed within 2 to 3 months of stopping treatment with Synarel. At the end of treatment 60% of patients treated with Synarel were symptom free, 32% had mild symptoms, 7% had moderate symptoms and 1% had severe symptoms.
   Of the 60% of patients who had complete relief of symptoms at the end of treatment, 17% had moderate symptoms at the end of the six month post-treatment period; 33% had mild symptoms; 50% were symptom free; no patient had severe symptoms.
8. Retreatment cannot be recommended since the safety of such retreatment is not known.
9. It is all right to use a nasal decongestant spray while you are being treated with Synarel if you follow these simple rules. Use Synarel first. Wait at least 2 hours after using Synarel before you use the decongestant spray.
10. You should avoid sneezing during or immediately after using Synarel, if possible, since sneezing may impair drug absorption.

Proper use of Synarel for Treatment of Endometriosis

1. When you start to use Synarel, the first dose should be taken between the second and fourth day after the beginning of your menstrual bleeding. You should continue taking Synarel every day as prescribed.
   Do not miss a single dose.
2. Unless your doctor has given you special instructions, follow the steps for using Synarel twice each day , about 12 hours between doses:
   • once in the morning in one nostril (for example, 7 am)
   • once in the evening in the other nostril (for example, 7 pm)
   The length of treatment is usually about 6 months, unless your doctor has given you special instructions.
3. Because it is so important that you do not miss a single dose of Synarel, here are some suggestions to help you remember:
   • Keep your Synarel in a place where you will be reminded to use it each morning and each evening — next to your toothbrush is one possibility.
   • Keep track of each dose on a calendar.
   • Make a note on your calendar on the day you start a new bottle of Synarel. You can also mark the date you started right on the bottle. Be sure to refill your prescription before the 30 days are up so you will have a new bottle on hand.
4. A bottle of Synarel should not be used for longer than 30 days (60 sprays). Each bottle contains sufficient quantity of nasal solution for initial priming of the pump and 30 days (60 sprays) of treatment. At the end of 30 days, a small amount of liquid will be left in the bottle. Do not try to use up that leftover amount because you might get too low a dose, which could interfere with the effectiveness of your treatment. Dispose of the bottle and do not reuse.
5. If your doctor increases your daily dose of Synarel, then your bottle will not last the standard 30 days. Please discuss this with your doctor to be sure that you have an adequate supply for uninterrupted treatment with Synarel to complete the recommended treatment period.

Preparation of the Synarel Nasal Spray unit

For use in your nose only.

Before you use Synarel nasal spray for the first time, you will need to prime it. This will ensure that you get the right dose of medicine each time you use it.

Important Tips about using Synarel

• Your pump should produce a fine mist, which can only happen by a quick and firm pumping action. It is normal to see some larger droplets of liquid within the fine mist. However, if Synarel comes out of the pump as a thin stream of liquid instead of a fine mist, Synarel may not work as well, and you should talk to your pharmacist.
• Be sure to clean the Spray Tip before and after every use . (See Step 4 ). Failure to do this may result in a clogged tip that may cause you not to get the right amount of medicine that is prescribed for you.
• The pump is made to deliver only a set amount of medicine, no matter how hard you pump it.
• Do Not try to make the tiny hole in the spray tip larger . If the hole is made larger the pump will deliver a wrong dose of Synarel.

图A

To Prime the Pump:

图B	1。 Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure B ).
图C	2。 Hold the bottle in an upright position away from you. Put two fingers on the "shoulders" of the spray bottle and put your thumb on the bottom of the bottle. Apply pressure evenly to the "shoulders" and push down quickly and firmly 7 to 10 times, until you see a fine spray. Usually you will see the spray after about 7 pumps. (See Figure C ).
	3。 The pump is now primed . Priming only needs to be done 1 time, when you start using a new bottle of Synarel . You will waste your medicine if you prime the pump every time you use it and may not have enough medicine for 30 days of treatment.
图D	4。 Clean the Spray Tip after Priming: Hold the bottle in a horizontal position. Rinse the spray tip with warm water while wiping the tip with your finger or soft cloth for 15 seconds. Wipe the spray tip with a soft cloth or tissue to dry. Replace the white safety clip and the clear plastic dust cover on the spray bottle (See Figure D ). Do Not try to clean the spray tip using a pointed object. Do Not take apart the pump.

How to use the Synarel Nasal Spray unit for the treatment of Endometriosis

药物状态

• 可用性 仅处方
• 怀孕和哺乳 现有风险数据
• CSA时间表* 不是管制药物
• 审批历史 FDA的药物史
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