ng cetrotide ® 0.25 mg with the enclosed needles and pre-filled syringe: wash hands thoroughly with soap and water. flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab. twist the injection needle with the yellow mark (20 gauge) on the pre-filled syringe. push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial. leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. avoid forming bubbles. draw the total contents of the vial into the syringe. if necessary, invert the vial and pull back the needle as far as needed to withdraw the entire contents of the vial. replace the needle with the yellow mark by the injection needle with the grey mark (27 gauge). invert the syringe and push the plunger until all air bubbles have been expelled. choose an injection site in the lower abdominal area, preferably around, but staying at least one inch away from the navel. choose a different injection site each day to minimize local irritation. use a second alcohol swab to clean the skin at the injection site and allow alcohol to dry. gently pinch up the skin surrounding the site of injection. inject the prescribed dose as directed by your doctor, nurse or pharmacist. use the syringe and needles only once. dispose of the syringe and needles properly after use. if available, use a medical waste container for disposal.

ild intensity and short duration. during post-marketing surveillance, cases of mild to moderate ovarian hyperstimulation syndrome and infrequent cases of hypersensitivity reactions including anaphylactoid reactions have been reported. two stillbirths were reported in phase 3 studies of cetrotide ® . congenital anomalies clinical follow-up studies of 316 newborns of women administered cetrotide ® were reviewed. one infant of a set of twin neonates was found to have anencephaly at birth and died after four days. the other twin was normal. developmental findings from ongoing baby follow-up included a child with a ventricular septal defect and another child with bilateral congenital glaucoma. four pregnancies that resulted in therapeutic abortion in phase 2 and phase 3 controlled ovarian stimulation studies had major anomalies (diaphragmatic hernia, trisomy 21, klinefelter syndrome, polymalformation, and trisomy 18). in three of these four cases, intracytoplasmic sperm injection (icsi) was the fertilization method employed; in the fourth case, in vitro fertilization (ivf) was the method employed. the minor congenital anomalies reported include: supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and qt syndrome. the causal relationship between the reported anomalies and cetrotide ® is unknown. multiple factors, genetic and others (including, but not limited to icsi, ivf, gonadotropins, and progesterone) make causal attribution difficult to study.

perties of cetrotide ® , which could result in fetal loss in humans as well. therefore, this drug should not be used in pregnant women.

f cetrotide ® on lh and fsh are reversible after discontinuation of treatment. in women, cetrotide ® delays the lh-surge, and consequently ovulation, in a dose-dependent fashion. fsh levels are not affected at the doses used during controlled ovarian stimulation. following a single 3 mg dose of cetrotide ® , duration of action of at least 4 days has been established. a dose of cetrotide ® 0.25 mg every 24 hours has been shown to maintain the effect. pharmacokinetics the pharmacokinetic parameters of single and multiple doses of cetrotide ® (cetrorelix acetate for injection) in adult healthy female subjects are summarized in table 1. table 1: pharmacokinetic parameters of cetrotide ® following 3 mg single or 0.25 mg single and multiple (daily for 14 days) subcutaneous (sc) administration. single dose 3 mg single dose 0.25 mg multiple dose 0.25 mg t max time to reach observed maximum plasma concentration t 1/2 elimination half-life c max maximum plasma concentration; multiple dose c ss, max auc area under the curve; single dose auc 0-inf , multiple dose auct cl total plasma clearance vz volume of distribution geometric mean (95% ci ln ), no. of subjects 12 12 12 t max median (min-max) [h] 1.5 (0.5-2) 1.0 (0.5-1.5) 1.0 (0.5-2) t 1/2 [h] 62.8 (38.2-108) 5.0 (2.4-48.8) 20.6 (4.1-179.3) c max [ng/ml] 28.5 (22.5-36.2) 4.97 (4.17-5.92) 6.42 (5.18-7.96) auc [ng∙h/ml] 536 (451-636) 31.4 (23.4-42.0) 44.5 (36.7-54.2) cl arithmetic mean, [ml/min∙kg] 1.28 based on iv administration (n=6, separate study 0013) vz [l/kg] 1.16 absorption cetrotide ® is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. the mean absolute bioavailability of cetrotide ® following subcutaneous administration to healthy female subjects is 85%. distribution the volume of distribution of cetrotide ® following a single intravenous dose of 3 mg is about 1 l/kg. in vitro protein binding to human plasma is 86%. cetrotide ® concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. following subcutaneous administration of cetrotide ® 0.25 mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer. metabolism after subcutaneous administration of 10 mg cetrotide ® to females and males, cetrotide ® and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours. in in vitro studies, cetrotide ® was stable against phase i- and phase ii-metabolism. cetrotide ® was transformed by peptidases, and the (1-4) peptide was the predominant metabolite. excretion following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine. in 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. the remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time. special populations pharmacokinetic investigations have not been performed either in subjects with impaired renal or liver function, or in the elderly, or in children (see precautions ). pharmacokinetic differences in different races have not been determined. there is no evidence of differences in pharmacokinetic parameters for cetrotide ® between healthy subjects and patients undergoing controlled ovarian stimulation. drug-drug interactions no formal drug-drug interaction studies have been performed with cetrotide ® (see precautions ). clinical studies seven hundred thirty two (732) patients were treated with cetrotide® (cetrorelix acetate for injection) in five (two phase 2 dose-finding and three phase 3) clinical trials. the clinical trial population consisted of caucasians (95.5%) and black, asian, arabian and others (4.5%). women were between 19 and 40 years of age (mean: 32). the studies excluded subjects with polycystic ovary syndrome (pcos), subjects with low or no ovarian reserve, and subjects with stage iii-iv endometriosis. two dose regimens were investigated in these clinical trials, either a single dose per treatment cycle or multiple dosing. in the phase 2 studies, a single dose of 3 mg was established as the minimal effective dose for the inhibition of premature lh surges with a protection period of at least 4 days. when cetrotide ® is administered in a multidose regimen, 0.25 mg was established as the minimal effective dose. the extent and duration of lh-suppression is dose dependent. in the phase 3 program, efficacy of the single 3 mg dose regimen of cetrotide ® and the multiple 0.25 mg dose regimen of cetrotide ® was established separately in two adequate and well controlled clinical studies utilizing active comparators. a third non-comparative clinical study evaluated only the multiple 0.25 mg dose regimen of cetrotide ®. the ovarian stimulation treatment with recombinant fsh or human menopausal gonadotropin (hmg) was initiated on day 2 or 3 of a normal menstrual cycle. the dose of gonadotropins was administered according to the individual patient's disposition and response. in the single dose regimen study, cetrotide ® 3 mg was administered on the day of controlled ovarian stimulation when adequate estradiol levels (400 pg/ml) were obtained, usually on day 7 (range day 5-12). if hcg was not given within 4 days of the 3 mg dose of cetrotide ® , then 0.25 mg of cetrotide ® was administered daily beginning 96 hours after the 3 mg injection until and including the day of hcg administration. in the two multiple dose regimen studies, cetrotide ® 0.25 mg was started on day 5 or 6 of cos. both gonadotropins and cetrotide ® were continued daily (multiple dose regimen) until the injection of human chorionic gonadotropin (hcg). oocyte pick-up (opu) followed by in vitro fertilization (ivf) or intracytoplasmic sperm injection (icsi) as well as embryo transfer (et) were subsequently performed. the results for cetrotide ® are summarized below in table 2. table 2: results of phase 3 clinical studies with cetrotide ® (cetrorelix acetate for injection) 3 mg in a single dose (sd) regimen and 0.25 mg in a multiple dose (md) regimen parameter cetrotide ® 3 mg (sd, active comparator study) cetrotide ® 0.25 mg (md, active comparator study) cetrotide ® 0.25 mg (md, non-comparative study) no. of subjects 115 159 303 hcg administered [%] 98.3 96.2 96.0 oocyte pick-up [%] 98.3 94.3 93.1 lh-surge [%] (lh ≥ 10 u/l and p progesterone ≥ 1 ng/ml) following initiation of cetrotide ® therapy 0.0 1.9 1.0 serum e 2 [pg/ml] at day hcg morning values , median with 5th – 95th percentiles 1125 (470-2952) 1064 (341-2531) 1185 (311-3676) serum lh [u/l] at day hcg , 1.0 (0.5-2.5) 1.5 (0.5-7.6) 1.1 (0.5-3.5) no. of follicles ≥ 11 mm at day hcg mean ± standard deviation 11.2±5.5 10.8±5.2 10.4±4.5 no. of oocytes: ivf icsi 9.2±5.2 10.0±4.2 7.6±4.3 10.1±5.6 8.5±5.1 9.3±5.9 fertilization rate: ivf icsi 0.48±0.33 0.66±0.29 0.62±0.26 0.63±0.29 0.60±0.26 0.61±0.25 no. of embryos transferred 2.6±0.9 2.1±0.6 2.7±1.0 clinical pregnancy rate [%] per attempt 22.6 20.8 19.8 per subject with et 26.3 24.1 23.3 in addition to ivf and icsi, one pregnancy was obtained after intrauterine insemination. in the five phase 2 and phase 3 clinical trials, 184 pregnancies have been reported out of a total of 732 patients (including 21 pregnancies following the replacement of frozen-thawed embryos). in the 3 mg regimen, 9 patients received an additional dose of 0.25 mg of cetrotide ® and two other patients received two additional doses of 0.25 mg cetrotide ® . the median number of days of cetrotide ® multiple dose treatment was 5 (range 1-15) in both studies. no drug related allergic reactions were reported from these clinical studies.

mean, [ml/min∙kg] 1.28 based on iv administration (n=6, separate study 0013) vz [l/kg] 1.16 absorption cetrotide ® is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. the mean absolute bioavailability of cetrotide ® following subcutaneous administration to healthy female subjects is 85%. distribution the volume of distribution of cetrotide ® following a single intravenous dose of 3 mg is about 1 l/kg. in vitro protein binding to human plasma is 86%. cetrotide ® concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. following subcutaneous administration of cetrotide ® 0.25 mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer. metabolism after subcutaneous administration of 10 mg cetrotide ® to females and males, cetrotide ® and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours. in in vitro studies, cetrotide ® was stable against phase i- and phase ii-metabolism. cetrotide ® was transformed by peptidases, and the (1-4) peptide was the predominant metabolite. excretion following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine. in 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. the remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time. special populations pharmacokinetic investigations have not been performed either in subjects with impaired renal or liver function, or in the elderly, or in children (see precautions ). pharmacokinetic differences in different races have not been determined. there is no evidence of differences in pharmacokinetic parameters for cetrotide ® between healthy subjects and patients undergoing controlled ovarian stimulation.

rapy is started on cycle day 2 or 3. cetrotide ® 0.25 mg is injected under the skin once daily , as directed by your physician. when an ultrasound examination shows that you are ready, another drug (hcg) is injected to induce ovulation. how should you use cetrotide ® ? you may self-inject cetrotide ® after special instruction from your doctor. to fully benefit from cetrotide ® , please read carefully and follow the instructions given below, unless your doctor advises you otherwise. cetrotide ® is for injection under the skin of the lower abdominal area, preferably around, but staying at least one inch away from the belly button. choose a different injection site each day to minimize local irritation. dissolve cetrotide ® powder only with the water contained in the pre-filled syringe. do not use a cetrotide ® solution if it contains particles or if it is not clear. before you inject cetrotide ® yourself, please read the following instructions carefully: directions for using cetrotide ® 0.25 mg with the enclosed needles and pre-filled syringe: 1. wash your hands thoroughly with soap and water. 2. on a clean flat surface, lay out everything you need (one vial of powder, one pre-filled syringe, one injection needle with a yellow mark, and one injection needle with a grey mark). 3. flip off the plastic cover of the vial. wipe the aluminum ring and the rubber stopper with an alcohol swab. 4. take the injection needle with the yellow mark and remove the wrapping. take the pre-filled syringe and remove the cover. twist the needle on the syringe and remove the cover of the needle. 5. push the needle through the center of the rubber stopper of the vial. inject the water into the vial by slowly pushing down on the plunger of the syringe. 6. leave the syringe in the vial. while carefully holding the syringe and vial, swirl gently to mix the powder and water together. when it is mixed, it will look clear and have no particles in it. do not shake or you will create bubbles in your medicine. 7. draw the total contents of the vial into the syringe. if liquid is left in the vial, invert the vial, pull back the needle until the opening of the needle is just inside the stopper. if you look from the side through the gap in the stopper, you can control the movement of the needle and the liquid. it is important to withdraw the entire contents of the vial. 8. detach the syringe from the needle and lay down the syringe. take the injection needle with the grey mark and remove its wrapping. twist the needle on the syringe and remove the cover of the needle. 9. invert the syringe and push the plunger until all air bubbles have been pushed out. do not touch the needle or allow the needle to touch any surface. 10. choose an injection site in the lower abdominal area, preferably around, but at least one inch away from the belly button. choose a different injection site each day to minimize local irritation. take a second alcohol swab and clean the skin at the injection site and allow alcohol to dry. inject the prescribed dose as directed by your doctor, nurse or pharmacist. 11. use the syringe and needles only once. dispose of the syringe and needles immediately after use (put the covers on the needles to avoid injury). a medical waste container should be used for disposal. special advice what do you do if you have used too much cetrotide ® ? contact your doctor in case of overdosage immediately to check whether an adjustment of the further ovarian stimulation procedure is required. possible side effects mild and short lasting reactions may occur at the injection site like reddening, itching, and swelling. nausea and headache have also been reported. call your doctor if you have any side effect not mentioned in this leaflet or if you are unsure about the effect of this medicine. storage how is cetrotide ® to be stored? store cetrotide ® in a cool dry place protected from excess moisture and heat. store cetrotide ® 0.25 mg in the refrigerator at 2-8°c (36-46°f). keep the packaged tray in the outer carton in order to protect it from light. how long may cetrotide ® be stored? do not use the cetrotide ® powder or the pre-filled syringe after the expiration date, which is printed on the labels and on the carton, and dispose of the vial and the syringe properly. how long can you keep cetrotide ® after preparation of the solution? the solution should be used immediately after preparation. store the medicine out of the reach of children. if you suspect that you may have taken more than the prescribed dose of this medicine, contact your doctor immediately. this medicine was prescribed for your particular condition. do not use it for another condition or give the drug to others. this leaflet provides a summary of the information about cetrotide ® . medicines are sometimes prescribed for uses other than those listed in the leaflet. if you have any questions or concerns, or want more information about cetrotide ® , contact your doctor or pharmacist. this leaflet has been approved by the u.s. food and drug administration. september 2018 figure figure figure figure figure figure figure figure figure figure figure