ema, and blurred vision. ( 5.4 ) 5.1 initial rise of gonadotropins and sex steroid levels during the early phase of initial therapy or after subsequent doses, gonadotropins and sex steroids may rise above baseline because of a transient stimulatory effect of the drug [see clinical pharmacology (12.2) ] . therefore, a transient increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during the first weeks of therapy or after subsequent doses. 5.2 psychiatric events psychiatric events have been reported in patients taking gnrh agonists, including triptorelin. post-marketing reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. monitor for development or worsening of psychiatric symptoms during treatment with triptodur [see adverse reactions (6) ] . 5.3 convulsions postmarketing reports of convulsions have been observed in patients receiving gnrh agonists, including triptorelin. these included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and ssris. convulsions have also been reported in patients in the absence of any of the conditions mentioned above [see adverse reactions (6) ] . 5.4 pseudotumor cerebri idiopathic intracranial hypertension pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients receiving gnrh agonists, including triptorelin. monitor patients for signs and symptoms of pseudotumor cerebri, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.

22.5 mg reconstituted with accompanying diluent (sterile water) 2 ml, and administered as a single intramuscular injection once every 24 weeks. triptodur treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician. 2.2 monitoring monitor response to triptodur with lh levels after a gnrh or gnrh agonist stimulation test, basal lh, or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, during therapy as necessary to confirm maintenance of efficacy, and with each subsequent dose. measure height (for calculation of growth rate) every 3-6 months and monitor bone age periodically. noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels. if the dose of triptodur is not adequate switching to an alternative gnrh agonist for the treatment of cpp with the ability for dose adjustment may be necessary. 2.3 reconstitution and administration instructions read these instructions completely before you begin. triptodur suspension will sediment very quickly and should be injected immediately after reconstitution in accordance with the detailed instructions below. if the sequence of steps to prepare the suspension is interrupted and/or the vial is put aside, the suspension will start to separate into diluent and microgranules. to minimize the risk of needle blockage during the injection, ensure that the preparation of the injection is not interrupted and/or the mixed suspension syringe is not put aside because the suspension will sediment quickly. use appropriate aseptic technique for preparation and administration. screw the plunger rod into the barrel end of the prefilled sterile water diluent syringe. to remove the cap, twist counterclockwise to separate from the luer lock on the syringe barrel. firmly attach one of the 21-gauge sterile safety needles onto the prefilled sterile water diluent syringe with a push and clockwise twist. this 21-gauge needle will only be used for reconstitution of the product. remove the plastic flip-off from the vial. disinfect the visible part of the stopper pull back on the safety cover towards the syringe and away from the 21-gauge needle. then pull the clear needle shield off. insert the 21-gauge needle through the stopper. inject the sterile water diluent into the vial, ensuring the diluent rinses the sides of the vial. do not release the plunger rod. if the syringe plunger is not maintained in position, it will naturally withdraw product into the syringe. thoroughly mix the vial with agitation for 30 to 60 seconds, ensuring the diluent rinses the sides of the vial. before moving on to the next step, check visually that the suspension appears milky and homogeneous without any visible aggregates or precipitates. if the suspension does not appear milky and homogeneous without any visible aggregates or precipitates, continue with the agitation. an up and down agitation can also be used to help eliminate aggregates or precipitates. the complete and homogeneous (milky) suspension of the product may require up to 60 seconds of agitation. important: once mixed, proceed to the next steps and administer without delay. the suspension will sediment very quickly so it is imperative to withdraw the suspension into the syringe directly after suspending the product in the vial. invert the vial and move back the syringe in order to position the end of the 21-gauge needle very near the level of the stopper, making sure the needle lumen is still completely in the vial. pull back the plunger rod slowly to withdraw the reconstituted product into the syringe, withdrawing as much of the reconstituted product into the syringe as possible. move the tip of the needle at the level of the stopper so as to be able to withdraw a maximum amount of suspension. withdraw the needle from the vial and push the safety cover forward toward the needle until you hear and/or feel it lock. then remove the first 21-gauge needle by grasping the needle hub to disconnect the needle from the syringe and discard it. this (first) 21-gauge needle will no longer be used. firmly attach the second sterile needle onto the syringe with a push and clockwise twist and pull back the safety cover towards the syringe. this 21-gauge needle will be used for administration. triptodur must only be administered with a thin-wall 21-gauge needle. do not prime the needle. inspect the suspension visually for particulate matter and discoloration. if the suspension does not appear milky and homogeneous, continue with an up and down agitation. if the suspension appears milky and homogeneous without visable aggregates or precipitates, administer the suspension immediately. inject the patient intramuscularly, preferably in either buttock or thigh using the entire contents of the syringe. the injection of the suspension should be performed rapidly and in a steady and uninterrupted manner in order to avoid any potential blockage of the needle. after administering the injection, immediately activate the safety cover: center your thumb or forefinger on the textured finger pad area of the safety cover and push it forward over the needle until you hear or feel it lock. use the one-handed technique and activate the mechanism away from yourself and others. immediately discard the syringe assembly into a suitable sharps container. image image image image image image image image image

d in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the safety of triptodur was evaluated in one uncontrolled, open-label single-arm clinical trial in which 44 children with central precocious puberty received two doses of triptodur and were observed for 12 months. the median age of the study population was 8 years (range 2-9 years) at treatment start; 88.6% of subjects were female, 59.1% were white, 27.3% were black and 4.5% were asian. table 1 shows all the adverse reactions that occurred in at least 2 patients (≥4.5%) during the open-label single-arm trial. table 1: adverse reactions injection site reactions are presented separately occurring in ≥ 2 patients treated with triptodur in an open-label single-arm trial adverse reactions number of patients reporting event (%) (total n=44) infections & infestations bronchitis 2 (4.5) gastroenteritis 3 (6.8) influenza 2 (4.5) nasopharyngitis 6 (13.6) otitis externa 2 (4.5) pharyngitis 2 (4.5) sinusitis 2 (4.5) upper respiratory tract infection 4 (9.1) nervous system disorders headache 6 (13.6) reproductive system & breast disorders menstrual (vaginal bleeding) includes % of patients with vaginal bleeding or menstrual disorder ("menstrual cycle returned") in 39 females out of n=44. 3 (7.7) respiratory, thoracic & mediastinal disorder cough 3 (6.8) vascular disorders hot flush 2 (4.5) other selected adverse reactions : injection site reactions injection site reactions occurring in patients immediately and/or 2 hours after injection include pain (45%), redness (14%), pruritus (2.3%) and swelling (2.3%). psychiatric disorders anxiety (2.3%) and mood altered (2.3%) 6.2 post-marketing experience the following adverse reactions have been identified during post-approval use of triptorelin. 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. hypersensitivity reactions: anaphylactic shock, anaphylactoid reaction, angioedema, urticaria. cardiovascular: hypertension. psychiatric: emotional lability, such as crying, irritability, impatience, anger, and aggression . depression, including rare reports of suicidal ideation and attempt. many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression. nervous system: convulsions , pseudotumor cerebri (idiopathic intracranial hypertension) vision disorders: visual impairment, visual disturbance

the period of organogenesis, maternal toxicity (decrease in body weight) and embryo-fetal toxicities (pre-implantation loss, increased resorption, and reduced number of viable fetuses) were observed at 100 mcg/kg, approximately 4 times the clinical dose based on body surface area. no embryonic and fetal developmental toxicities were observed in mice at doses up to 4 times the clinical dose. teratogenic effects were not observed in viable fetuses in rats or mice. 8.2 lactation risk summary there are no data on the presence of triptorelin in human milk, or the effects of the drug on the breastfed infant, or on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for triptodur and any potential adverse effects on the breastfed child from triptodur or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of triptodur have been established in pediatric patients 2 years of age and older based on a single-arm open-label study of 44 children 2-9 years of age with cpp [see clinical studies (14) ] . the safety and effectiveness of triptodur have not been established in pediatric patients less than 2 years old. 8.6 renal impairment triptodur has not been studied in children with renal impairment. adult subjects with renal impairment had higher exposure than young healthy adult males [see clinical pharmacology (12.3) ]. 8.7 hepatic impairment triptodur has not been studied in children with hepatic impairment. adult subjects with hepatic impairment had higher exposure than young healthy adult males [see clinical pharmacology (12.3) ].

maternal toxicity (decrease in body weight) and embryo-fetal toxicities (pre-implantation loss, increased resorption, and reduced number of viable fetuses) were observed at 100 mcg/kg, approximately 4 times the clinical dose based on body surface area. no embryonic and fetal developmental toxicities were observed in mice at doses up to 4 times the clinical dose. teratogenic effects were not observed in viable fetuses in rats or mice.

c mean serum triptorelin levels were 0.11, 0.17, 0.05 and 0.03 ng/ml at months 1, 2, 3, and 6, respectively. distribution there is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins. elimination metabolism the metabolism of triptorelin in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome p450). thus far no metabolites of triptorelin have been identified. pharmacokinetic data suggest that c-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in plasma, or cleared by the kidneys. excretion triptorelin is eliminated by both the liver and the kidneys. following intravenous administration of 0.5 mg triptorelin peptide to six healthy male volunteers with a creatinine clearance of 149.9 ml/min, 41.7% of the dose was excreted in urine as intact peptide with a total triptorelin clearance of 211.9 ml/min. this percentage increased to 62.3% in patients with liver disease who have a lower creatinine clearance (89.9 ml/min). it has also been observed that the nonrenal clearance of triptorelin (patient anuric, cl creat = 0) was 76.2 ml/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver. specific populations renal impairment after intravenous bolus injection of 0.5 mg triptorelin in adults, the two distribution half-lives were unaffected by renal impairment. however, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as increases in volume of distribution and consequently, an increase in the elimination half-life. adult male subjects with moderate or severe renal impairment had approximately 2-fold higher exposure (auc values) than young healthy adult males (see table 1 ) [see use in specific populations (8.6) ]. hepatic impairment after intravenous bolus injection of 0.5 mg triptorelin in adults, the two distribution half-lives were unaffected by hepatic impairment. in adult males with hepatic insufficiency, triptorelin clearance was reduced and exposure (auc) was increased 3.7-fold compared to young healthy adult males (table 2) [see use in specific populations (8.7) ] . table 2: pharmacokinetic parameters (mean ± sd) in healthy adults, adults with renal impairment, and adults with hepatic impairment following an i.v. bolus of 0.5 mg triptorelin in solution group c max (ng/ml) auc inf (h∙ng/ml) cl p (ml/min) cl renal (ml/min) t 1/2 (h) cl creat (ml/min) 6 healthy male volunteers 48.2 ±11.8 36.1 ±5.8 211.9 ±31.6 90.6 ±35.3 2.81 ±1.21 149.9 ±7.3 6 males with moderate renal impairment 45.6 ±20.5 69.9 ±24.6 120.0 ±45.0 23.3 ±17.6 6.56 ±1.25 39.7 ±22.5 6 males with severe renal impairment 46.5 ±14.0 88.0 ±18.4 88.6 ±19.7 4.3 ±2.9 7.65 ±1.25 8.9 ±6.0 6 males with liver disease 54.1 ±5.3 131.9 ±18.1 57.8 ±8.0 35.9 ±5.0 7.58 ±1.17 89.9 ±15.1 drug-drug interactions in vitro assessment of drug interactions drug metabolizing enzyme inhibition triptorelin did not inhibit cyp1a2, 2b6, 2c8, 2c9, 2c19 or 2d6, or cyp 3a4/5 at clinically relevant concentrations. drug metabolizing enzyme induction in fresh human hepatocytes from three human donors, triptorelin did not induce cyp1a2 or cyp3a4/5 activity. transporters triptorelin was a poor p-gp substrate and had no inhibitory effect toward p-gp.

c data suggest that c-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in plasma, or cleared by the kidneys. excretion triptorelin is eliminated by both the liver and the kidneys. following intravenous administration of 0.5 mg triptorelin peptide to six healthy male volunteers with a creatinine clearance of 149.9 ml/min, 41.7% of the dose was excreted in urine as intact peptide with a total triptorelin clearance of 211.9 ml/min. this percentage increased to 62.3% in patients with liver disease who have a lower creatinine clearance (89.9 ml/min). it has also been observed that the nonrenal clearance of triptorelin (patient anuric, cl creat = 0) was 76.2 ml/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver. specific populations renal impairment after intravenous bolus injection of 0.5 mg triptorelin in adults, the two distribution half-lives were unaffected by renal impairment. however, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as increases in volume of distribution and consequently, an increase in the elimination half-life. adult male subjects with moderate or severe renal impairment had approximately 2-fold higher exposure (auc values) than young healthy adult males (see table 1 ) [see use in specific populations (8.6) ]. hepatic impairment after intravenous bolus injection of 0.5 mg triptorelin in adults, the two distribution half-lives were unaffected by hepatic impairment. in adult males with hepatic insufficiency, triptorelin clearance was reduced and exposure (auc) was increased 3.7-fold compared to young healthy adult males (table 2) [see use in specific populations (8.7) ] . table 2: pharmacokinetic parameters (mean ± sd) in healthy adults, adults with renal impairment, and adults with hepatic impairment following an i.v. bolus of 0.5 mg triptorelin in solution group c max (ng/ml) auc inf (h∙ng/ml) cl p (ml/min) cl renal (ml/min) t 1/2 (h) cl creat (ml/min) 6 healthy male volunteers 48.2 ±11.8 36.1 ±5.8 211.9 ±31.6 90.6 ±35.3 2.81 ±1.21 149.9 ±7.3 6 males with moderate renal impairment 45.6 ±20.5 69.9 ±24.6 120.0 ±45.0 23.3 ±17.6 6.56 ±1.25 39.7 ±22.5 6 males with severe renal impairment 46.5 ±14.0 88.0 ±18.4 88.6 ±19.7 4.3 ±2.9 7.65 ±1.25 8.9 ±6.0 6 males with liver disease 54.1 ±5.3 131.9 ±18.1 57.8 ±8.0 35.9 ±5.0 7.58 ±1.17 89.9 ±15.1 drug-drug interactions in vitro assessment of drug interactions drug metabolizing enzyme inhibition triptorelin did not inhibit cyp1a2, 2b6, 2c8, 2c9, 2c19 or 2d6, or cyp 3a4/5 at clinically relevant concentrations. drug metabolizing enzyme induction in fresh human hepatocytes from three human donors, triptorelin did not induce cyp1a2 or cyp3a4/5 activity. transporters triptorelin was a poor p-gp substrate and had no inhibitory effect toward p-gp.

cycles prior to mating, triptorelin at doses of 2, 20, and 200 mcg/kg (approximately 0.07, 0.7, and 7 times the estimated human daily dose based on body surface area) or two monthly injections as slow release microspheres (~20 mcg/kg/day) had no effect on the fertility or general reproductive function of female rats. no studies were conducted to assess the effect of triptorelin on male fertility.

riptorelin at doses of 2, 20, and 200 mcg/kg (approximately 0.07, 0.7, and 7 times the estimated human daily dose based on body surface area) or two monthly injections as slow release microspheres (~20 mcg/kg/day) had no effect on the fertility or general reproductive function of female rats. no studies were conducted to assess the effect of triptorelin on male fertility.

aturation at month 12. table 3: efficacy of triptodur 22.5 mg administered every 6 months to children with cpp intent-to-treat population endpoint % (n/n) of children achieving endpoint month 1 month 2 month 3 month 6 month 9 month 12 % with prepubertal lh (gnrh-stim lh ≤5 iu/l) 95% (42/44) 95% (42/44) 95% (42/44) 93% primary efficacy endpoint (41/44) 95% (42/44) 98% (43/44) % girls with prepubertal estradiol (<20 pg/ml) 87% (34/39) 89% (34/38) 92% (36/39) 79% (31/39) 82% (32/39) 79% (31/39) % boys with prepubertal testosterone (<30 ng/dl) 80% (4/5) 80% (4/5) 100% (5/5) 100% (5/5) 80% (4/5) 80% (4/5) % with no increase in ba/ca bone age/chronological age ratio vs. baseline 64% (28/44) 95% (42/44) % achieving stabilization of sexual maturation 91% (40/44) 89% (39/44) % girls with regression of uterine length 69% (27/39) 77% (30/39) % boys with no progression in testis volumes 100% (5/5) 100% (5/5) following the second triptodur injection, 22 children (all girls) were assessed for evidence of an acute-on-chronic phenomenon (i.e., increase in basal lh >5 iu/l or serum estradiol level >20 pg/ml 48 hours after the second triptorelin injection). of these, one girl who achieved prepubertal hormone levels prior to the second injection showed biochemical evidence of acute-on-chronic phenomenon [see warnings and precautions (5.2) and adverse reactions (6.1) ] .

pment or worsening of psychiatric symptoms, including depression, during treatment with triptodur [see warnings and precautions (5.2) and adverse reactions (6.2) ]. convulsions inform caregivers that reports of convulsions have been observed in patients receiving gnrh agonists, including triptorelin. patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions may be at increased risk [see warnings and precautions (5.3) ]. pseudotumor cerebri (idiopathic intracranial hypertension) inform patients and caregivers that reports of pseudotumor cerebri (idiopathic intracranial hypertension) have been observed in pediatric patients receiving gnrh agonists, including triptorelin. monitor patients for signs and symptoms of pseudotumor cerebri, including headache, and vision issues such as blurred vision, double vision, loss of vision, pain behind the eye or pain with eye movement, ringing in the ears, dizziness, and nausea. advise patients and caregivers to contact their healthcare provider if the patient develops any of these symptoms. [see warnings and precautions (5.4) ] . pregnancy is contraindicated triptodur is contraindicated in pregnancy. if the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to fetus [see use in specific populations (8.1) ]. compliance with the dosing schedule inform caregivers about the importance of adherence to the triptodur dosing schedule of one injection every 24 weeks. patients should not miss or delay a scheduled dose.