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藥物科學 The Risk of Atropine-Induced Acute Angle-Closure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma The Risk of Atropine-Induced Acute AngleClosure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma Hung-Yi Chen Department of Pharmacy, National Cheng Kung University Hospital Abstract Irinotecan was approved by FDA as the first line therapy in combination with fluorouracil and leucovorin for metastatic colon or rectal cancer patients. Atropine is given for management of irinotecan-induced cholinergic syndrome, however, it is contraindicated for patient with angle-closure glaucoma. It is necessary to weigh the benefit before making a clinical decision. In this article, we are going to discuss whether it is appropriate to use atropine in colon cancer patients with history of angle-closure glaucoma before irinotecan therapy. Keywords: colorectal cancer, irinotecan, atropine, angle-closure glaucoma that can be ameliorate by atropine, this Introduction Irinotecan was approved by FDA as the first line therapy in combination with fluorouracil and leucovorin for metastatic colon or rectal cancer patients. Irinotecan is also given as off-lable use for esophageal cancer, gastric suggests that irinotecan directly interacts with acetylcholinesterase (AChE). And this hypothesis was confirmed by a series of detail 2 kinetic analyses with irinotecan . Diarrhea is one of the most concerned effect, the cancer, pancreatic cancer, cervical cancer, relationship between the pharmacokinetics of ovarian cancer (recurrent), glioblastoma, Ewing irinotecan and its metabolites (such as SN38) sarcoma, rhabdomyosarcoma, non-small cell and diarrhea is also quite complex. Both 1 lung cancer, and small cell lung cancer . irinotecan and its metabolite, SN-38 undergo One of the most well-known side effects enterohepatic circulation, and the concentration of irinotecan is cholinergic syndrome. Since a of SN-38 has been correlated with diarrhea cholinergic syndrome rapidly occurs following in mice and in humans . These side effects high dose of irinotecan administration can be easily managed with atropine. Thus, 3 第 32 卷第 1 期 Mar. 31 2016 藥學雜誌 第126冊 49 藥物科學 Pharmaceutical Sciences atropine is widely used in irinotecan-containing affect the willingness of patients to receive the chemotherapy regimens. next course of chemotherapy. Incidence rate of cholinergic syndrome Incidence rate of cholinergic syndrome, Literature review: Atropine induced acute angle-closure glaucoma such as early diarrhea, perspiration, abdominal Several case reports have mentioned about cramps, hiccup, visual accommodation atropine induced acute angle-closure glaucoma disturbances, and lacrimation, ranges from 1.4% in precipitated patients . They cause our concern 4,5 to 60% in patients receiving irinotecan . of acute angle-closure glaucoma (AACG) when These side effects usually occur just after colon cancer patients are receiving atropine. A irinotecan infusion are not life-threatening and summary of these atropine-induced AACG case can be managed well in hospital, however, can reports are listed on Table 1. Table 1. Summary of atropine induced acute angle-closure glaucoma-case reports Age & Sex History Routine drugs Chief complain 62 y/o, Female Obstructive pulmonary disease, routine ophthalamic examination of shallow anterior chambers, angleclosure glaucoma, laser iridotomy in the right eye only 4% pilocarpine, 0.1% dipivefrin (to increase humor outflow) Decompensation obstructive lung disease Aerosolized atropine, 2.5 mg q4h 57 y/o, Female Long-standing, steroid dependent, obstructive pulmonary disease, routine eye examination of shallow anterior chambers - 6,7 66 y/o, Male Acute myocardial infarction with thrombolytic therapy, Ballon angioplasty was performed for recurred chest pain - Acute respiratory failure Bradycardia during requiring intubation angioplasty Suspected drug Aerosolized atropine, 2 mg q4h IV atropine 0.5 mg, 0.5 mg, 0.3 mg in a 40-mins time period AACG onset time 3rd hospital day 5th hospital day Shortly after administration Symptoms and Hyperemia with corneal edema in Hyperemic left eye with Right eye pain, blurred signs left eye, Increasing pain in her left mild photophobia, ocular vision of the right eye, of AACG eye, an intense, unilateral, left-side surface pain, and a discharge. headache, conjunctival headache; blurred vision and nausea. (Misdiagnosis as conjunctivitis, hyperemia, dilated and fixed Left pupil was mildly dilated at 5 then 10% sulfacetamide right pupil mm, with minimal reaction to light. solution for 4 days) IOP 32 mmHg IOP 10/28 mmHg Management IV acetazolamide 500 mg , 2% 2% pilocarpine HCl QID OS, Laser iridotomy was pilocarpine HCl, 0.5% Timolol, laser iridotomy was performed performed 20% mannitol 1 g/kg x 2 doses; 2% in the left eye pilocarpine Q3H、1% prednisolone QID until iridectomy was performed *AACG = acute angle-closure glaucoma;IOP = intraocular pressure 50 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar. 31 2016 藥物科學 The Risk of Atropine-Induced Acute Angle-Closure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma It is noteworthy that, an acute ACG attack was triggered in one patient by aerosolized atropine and oxybutynin caused another ACG attack, even though the patient received pilocarpine HCl miotic therapy routinely. Dosing regimen of atropine for cholinergic syndrome In Taiwan, atropine is used when patients suffer from cholinergic syndrome. In some hospitals, while it could be routinely prescribed at the first time and subsequent courses of chemotherapy. There are two administration routes to deliver atropine, intravenous and subcutaneous route. There are not any dosage difference in each route. The most consentaneous dosage of atropine is 0.5 mg and 0.25 mg. Though atropine dosage ranges from 0.2 mg to 2 mg regardless of administration route in literatures 9,10 . Should we use atropine for colon cancer patients receiving irinotecan with history of angle-closure glaucoma? We proposed several reasons to support the use of atropine in colon cancer with history of angle closure glaucoma, and some reasons to hold atropine in these patients. These considerations are listed on Table 2. Table 2. Factors should be considered in colon cancer patients going to use atropine with history of angle-closure glaucoma. Use atropine before irinotecan Diarrhea may cause dehydration, electrolyte imbalance which maybe fetal Incidence of irinotecan induced cholinergic syndrome (1.4-60%) is higher than atropine induced AACG (< 0.1%)9. Patient may delayed chemotherapy regimen because of displeasure cholinergic syndrome. It is unclear if low dose systemic atropine (< 0.6 mg) cause ocular effects. Conventional systemic dose of atropine (0.6 mg) have little ocular effect. Pilocarpine eye drops could be given to patient before subcutaneous atropine to reduce the possibility of ocular events. There is no case report of single dose of subcutaneous atropine induced acute glaucoma. Do not use atropine before irinotecan AACG is serious and could lead to irreversible loss of vision. The premedication, diphenydramine is also with anticholinergic effect, to combine with atropine may increase risk of AACG which may cause visual loss. Cholinergic symptoms are reversible. Atropine is labled as contraindication in angle-closure glaucoma patients in package insert. *AACG=acute angle closure glaucoma Alternative agents Cheng et al. conducted a retrospective, single-center, nonrandomized, cohort study of adult patients (N = 80) treated with oral atropine 0.025 mg-diphenoxylate 0.25 mg or hyoscyamine as premedication before receiving irinotecan (total 532 cycles). Incidence of cholinergic syndrome did not differ between atropine-diphenoxylate and hyoscyamine groups after the first cycle or after the entire treatment course. There was a higher percentage of diarrhea but less abdominal pain or cramping and diaphoresis reported in the hyoscyamine group compared with the atropine-diphenoxylate group among patients who developed cholinergic syndrome. It is worth noting that additional premedications with intravenous atropine 0.5 mg were not required for subsequent irinotecan cycles in 第 32 卷第 1 期 Mar. 31 2016 藥學雜誌 第126冊 51 藥物科學 Pharmaceutical Sciences the hyoscyamine group, compared with the atropine routinely if the patient suffers from 23.3% of patients in the atropine-diphenoxylate cholinergic syndrome which may impede him 11 group . Theoretically, atropine-diphenoxylate to receive further courses of chemotherapy. We and hyoscyamine both could result in enlarged recommend that pilocarpine 2% eye drops could pupils of the eyes and elevate ocular pressure. be given before starting atropine to reduced risk This article gave us a hint that two medications of AACG in colon cancer patients with history sharing similar mechanism could result in of angle-closure glaucoma as shown in Figure different side effect profile. Though the risk 1 4,6,7 . of atropine, diphenoxylate and hyoscyamineinduced AACG are still unknown. To date, there is not any research could answer which premedication is the best for patient with history of ACG before irinotecan infusion. Conclusion In summary, we didn't find any case report of subcutaneously administered atropineinduced AACG. However, it is unclear if low dose systemic atropine (< 0.6 mg) could cause ocular effects. Since incidence of cholinergic syndrome in not high, we recommend to hold atropine in colon cancer patient with history of angle-closure glaucoma who are going to for receive irinotecan, and to give a lower dose of Figure 1. Flow chart of atropine use in colon cancer patients receiving irinotecan with history of angle-closure glaucoma 有閉鎖性青光眼病人接受 irinotecan 時 使用 atropine 而誘發 AACG 的風險 成大醫院藥劑部藥師 陳弘益 摘要 美國 FDA 核准 irinotecan 與 fluorouracil 和 leucovorin 用於轉移性大腸直腸癌之第 一線治療,atropine 則被用於緩解 irinotecan 引起的膽鹼症候群,然而 atropine 對於閉 52 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.1 Mar. 31 2016 藥物科學 The Risk of Atropine-Induced Acute Angle-Closure Glaucoma in Irinotecan User with History of Angle-Closure Glaucoma 鎖性青光眼的病人而言屬於禁忌,使用前應評估好壞處的風險效益,本文我們將討論 有閉鎖性青光眼病史的大腸直腸癌病人,預計接受 irinotecan 治療時,是否應該使用 atropine。 Reference: 1. Irinotecan: Drug information In: UpToDate, Post TW glaucoma complicating systemic atropine use in the car- (Ed), UpToDate, Waltham, MA. (Accessed on January 19, diac catheterization laboratory. Cathet Cardiovasc Diagn. 2015.) 2. 3. Hyatt JL, Tsurkan L, Morton CL et al: Inhibition of ace- 1996; 39:262-264. 8. 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Use of atropine-diphenox- Berdy GJ, Berdy SS, Odin LS, et al: Angle closure glau- ylate compared with hyoscyamine to decrease rates of coma precipitated by aerosolized atropine. Arch Intern irinotecan-related cholinergic syndrome. J Community Med 1991; 151:1658-1660. Support Oncol. 2015(1):3-7. Mandak JS, Minerva P, Wilson TW, et al: Angle closure 第 32 卷第 1 期 Mar. 31 2016 藥學雜誌 第126冊 53