2.1       Dosing Information

TRELSTAR must be administered under the supervision of a physician.

TRELSTAR is administered by a single intramuscular injection in either buttock.  Dosing schedule depends on the product strength selected (Table 1).  The lyophilized microgranules are to be reconstituted in sterile water.  No other diluent should be used. 

Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule.

The suspension should be administered immediately after reconstitution.

As with other drugs administered by intramuscular injection, the injection site should be alternated periodically.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2       Reconstitution Instructions for TRELSTAR with MIXJECT® SYSTEM

Important: Please read the instructions completely and prepare the patient before you begin the MIXJECT activation and drug administration procedure.

MIXJECT Preparation and Activation

Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection.  Place the sealed tray on a clean, flat surface that is covered with a sterile pad or cloth.  Peel the cover away from the tray and remove the MIXJECT components and the TRELSTAR vial. 

	STEP 1 – PREPARE VIAL Remove the flip-off button cap from the vial, revealing the rubber stopper. Place the vial in a standing upright position on the prepared surface. Disinfect the rubber stopper with the alcohol wipe. Discard the alcohol wipe and allow the stopper to dry.
	STEP 2 – APPLY MIXJECT VIAL ADAPTER Peel the cover away from the blister pack containing the vial adapter. Do not remove the vial adapter from the blister pack. On a level surface, place the blister pack containing the vial adapter firmly on the vial top. Ensure the spike is centered and vertical when piercing the vial. Push down gently until you feel it snap into place. Remove the blister pack from the vial adapter. Ensure luer lock for needle connection is tight.
	STEP 3 – PREPARE SYRINGE BARREL (a) Screw the plunger rod into the gray stopper in the barrel end of the syringe. Grasp the plastic ‘spin lock’ collar on the syringe barrel with index finger and thumb, unscrew and discard the gray rubber cap from the syringe barrel. (b) Maintain your grip on the spin lock, ensuring that you have clear visibility of the connection. Attach the syringe to the vial adapter by screwing the spin lock clockwise into the opening on the side of the vial adapter. Gently twist the syringe until it stops turning to ensure a tight connection. (Overtightening can result in a poor connection and leakage)
	STEP 4 – TRANSFER DILUENT TO VIAL While keeping the syringe and vial securely coupled in an upright position, slowly push the plunger to transfer all of the diluent into the vial. Ensure that diluent rinses the sides of the vial. Keep the plunger rod depressed and do not release the plunger rod.
	STEP 5 – MIX TRELSTAR SUSPENSION Keep the plunger rod depressed, grip the vial and vial adapter firmly and shake vigorously for 30 seconds to mix the contents thoroughly. This will ensure complete mixing of TRELSTAR and the sterile water diluent. The suspension should appear homogeneous and milky. In order to avoid separation of the suspension, proceed to the next steps without delay. The product must be injected within less than 2 minutes from reconstitution. Note: If there is sedimentation in the vial, shake again.
	STEP 6 – LOAD THE SYRINGE WITH TRELSTAR (a) Invert the MIXJECT system so that the vial is at the top. Hold the MIXJECT system firmly by the luer lock connection and syringe barrel and pull back the plunger rod slowly to draw the reconstituted TRELSTAR into the syringe while maintaining pressure on the plunger. (b) Rotate MIXJECT system so syringe is vertical. Remove air bubbles by expelling air into the vial but do not propel the suspension beyond the luer lock.
	STEP 7 – DISCONNECT VIAL ADAPTER Return the vial to its upright position. Hold the barrel and luer lock firmly.  With your other hand, disconnect the vial adapter and vial from the MIXJECT syringe by grasping the plastic cap of the vial adapter and turning it clockwise. Grasp only the vial adapter cap when removing.
	STEP 8 – PREPARE NEEDLE FOR INJECTION Make sure that the patient is ready for the administration. Just prior to administration, perform at least 5 inversions with the syringe to resuspend the particles. Lift up the safety cover and remove the clear plastic needle shield by pulling it from the assembly. The safety cover should be perpendicular to the needle, with the needle facing away from you. Do not prime the needle.  The syringe containing the TRELSTAR suspension is now ready for administration. The suspension should be administered immediately (less than 2 minutes) after reconstitution to avoid excessive thickening of the suspension.
	STEP 9 – ADMINISTRATION Administer the injection by inserting the needle at a 90-degree angle into the large gluteal muscle. Ensure that the full amount of the product is injected within 10 seconds without interruption. Injection sites should be alternated.
	STEP 10 – SAFETY LOCK AFTER INJECTION After administering the injection, immediately activate the safety mechanism by centering your thumb or forefinger on the textured finger pad area of the safety cover and pushing it forward over the needle until you hear or feel it lock in place. Use the one-handed technique and activate the mechanism away from yourself and others. Immediately discard the syringe into a sharps container after a single use.

4.1       Hypersensitivity

TRELSTAR is contraindicated in individuals with a known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH [see Warnings and Precautions (5.1)].

5.1       Hypersensitivity Reactions

Anaphylactic shock, hypersensitivity, and angioedema related to triptorelin administration have been reported.  In the event of a hypersensitivity reaction, therapy with TRELSTAR should be discontinued immediately and the appropriate supportive and symptomatic care should be administered. 

5.2       Tumor Flare

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels [see Clinical Pharmacology  (12.2)]. As a result, isolated cases of worsening of signs and symptoms of prostate cancer during the first weeks of treatment have been reported with GnRH agonists.  Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.

5.3       Metabolic Syndrome

The use of GnRH agonists may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset of diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving a GnRH agonist and manage according to institutional guidelines.

5.4       Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current institutional guidelines.

5.5       Effect on QT/QTc Interval

Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. 

5.6       Laboratory Tests

Monitor serum levels of testosterone following injection of TRELSTAR. In the majority of patients, testosterone levels increased above baseline, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks [see Clinical Studies (14) and Adverse Reactions (6)]. 

5.7       Laboratory Test Interactions

Chronic or continuous administration of triptorelin in therapeutic doses results in suppression of pituitary-gonadal axis.  Diagnostic tests of the pituitary-gonadal function conducted during treatment and after cessation of therapy may therefore be misleading.

5.8       Embryo-Fetal Toxicity

Based on findings from animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman [Clinical Pharmacology (12.1)]. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)].

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of the three TRELSTAR formulations was evaluated in clinical trials involving patients with advanced prostate cancer.  Mean testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment.  The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction. Isolated cases of spinal cord compression with weakness or paralysis of the lower extremities have occurred [see Warnings and Precautions (5.3)].

Adverse reactions reported for each of the three TRELSTAR formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4.  Often, causality is difficult to assess in patients with metastatic prostate cancer.  The majority of adverse reactions related to triptorelin are a result of its pharmacological action, i.e., the induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved. Local reactions at the injection site or allergic reactions may occur.

The following adverse reactions were reported to have a possible or probable relationship to therapy as ascribed by the treating physician in at least 1% of patients receiving TRELSTAR 3.75 mg.

*  Adverse reactions for TRELSTAR 3.75 mg are coded using the WHO Adverse Reactions Terminology (WHOART)

The following adverse reactions were reported to have a possible or probable relationship to therapy as ascribed by the treating physician in at least 1% of patients receiving TRELSTAR 11.25 mg.

*  Adverse reactions for TRELSTAR 11.25 mg are coded using the WHO Adverse Reactions Terminology (WHOART)

The following adverse reactions occurred in at least 5% of patients receiving TRELSTAR 22.5 mg. The table includes all reactions whether or not they were ascribed to TRELSTAR by the treating physician. The table also includes the incidence of these adverse reactions that were considered by the treating physician to have a reasonable causal relationship or for which the relationship could not be assessed. 

*  Adverse reactions for TRELSTAR 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA)

Changes in Laboratory Values During Treatment

The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients:

TRELSTAR 3.75 mg: There were no clinically meaningful changes in laboratory values detected during therapy.

TRELSTAR 11.25 mg: Decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase at the Day 253 visit.

TRELSTAR 22.5 mg: Decreased hemoglobin and increased glucose and hepatic transaminases were detected during the study. The majority of the changes were mild to moderate. 

6.2       Post marketing Experience

The following adverse reactions have been identified during post approval use of gonadotropin releasing hormone agonists. 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.

Pituitary Apoplexy – During postmarketing 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 System – cerebrovascular accident, myocardial infarction, pulmonary emboli, thromboembolic events (including deep venous thrombosis, transient ischemic attack, and thrombophlebitis)

Central/Peripheral Nervous System – convulsions

Hepatobiliary Disorder – non-alcoholic fatty liver disease

Respiratory, Thoracic, and Mediastinal Disorder – interstitial lung disease

8.1       Pregnancy

Risk Summary

Based on findings in animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Data

Animal Data

Studies in pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area) during the period of organogenesis demonstrated maternal toxicity and embryo-fetal toxicities.  Embryo-fetal toxicities consisted of pre-implantation loss, increased resorption, and reduced mean number of viable fetuses at the high dose.  Teratogenic effects were not observed in viable fetuses in rats or mice.  Doses administered to mice were 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, and 7 times the estimated human daily dose based on body surface area).    

8.2       Lactation

The safety and efficacy of TRELSTAR have not been established in females.  There are no data on the presence of triptorelin in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child.  Because of the potential for serious adverse reactions in a breastfed child from TRELSTAR, a decision should be made to either discontinue breastfeeding, or discontinue the drug taking into account the importance of the drug to the mother.

8.3       Females and Males of Reproductive Potential

Infertility

Males

Based on mechanism of action, TRELSTAR may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1)].

8.4       Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5       Geriatric Use

Prostate cancer occurs primarily in an older population.  Clinical studies with TRELSTAR have been conducted primarily in patients ≥ 65 years [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.6       Renal Impairment

Subjects with renal impairment had higher exposure than young healthy males [see Clinical Pharmacology (12.3)].

8.7       Hepatic Impairment

Subjects with hepatic impairment had higher exposure than young healthy males [see Clinical Pharmacology (12.3)].

12.1       Mechanism of Action

Triptorelin is a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH).  Comparative in vitro studies showed that triptorelin was 100-fold more active than native GnRH in stimulating luteinizing hormone release from monolayers of dispersed rat pituitary cells in culture and 20-fold more active than native GnRH in displacing 125I-GnRH from pituitary receptor sites.  In animal studies, triptorelin pamoate was found to have 13‑fold higher luteinizing hormone-releasing activity and 21-fold higher follicle-stimulating hormone-releasing activity compared to the native GnRH.

12.2       Pharmacodynamics

Following the first administration, there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol [see Adverse Reactions (6)].  After chronic and continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular steroidogenesis are observed.  A reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained.  Consequently, the result is that tissues and functions that depend on these hormones for maintenance become quiescent.  These effects are usually reversible after cessation of therapy.

Following a single intramuscular injection of TRELSTAR:

TRELSTAR 3.75 mg: serum testosterone levels first increased, peaking on Day 4, and declined thereafter to low levels by Week 4 in healthy male volunteers.

TRELSTAR 11.25 mg: serum testosterone levels first increased, peaking on Days 2 – 3, and declined thereafter to low levels by Weeks 3 – 4 in men with advanced prostate cancer.

TRELSTAR 22.5 mg: serum testosterone levels first increased, peaking on Day 3, and declined thereafter to low levels by Weeks 3 – 4 in men with advanced prostate cancer.

12.3       Pharmacokinetics

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours. 

Absorption

Following a single intramuscular injection of TRELSTAR to patients with prostate cancer, mean peak serum concentrations of 28.4 ng/mL, 38.5 ng/mL, and 44.1 ng/mL occurred in 1 to 3 hours after the 3.75 mg, 11.25 mg, and 22.5 mg formulations, respectively. 

Triptorelin did not accumulate over 9 months (3.75 mg and 11.25 mg) or 12 months (22.5 mg) of treatment.

Distribution

The volume of distribution following a single intravenous bolus dose of 0.5 mg of triptorelin peptide was 30 – 33 L in healthy male volunteers.  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 P-450). The effect of triptorelin on the activity of other drug metabolizing enzymes is also unknown.  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, CIcreat = 0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver.

Special Populations

Age and Race

The effects of age and race on triptorelin pharmacokinetics have not been systematically studied.  However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicate that triptorelin was eliminated twice as fast in this young population as compared with patients with moderate renal insufficiency.  This is related to the fact that triptorelin clearance is partly correlated to total creatinine clearance, which is well known to decrease with age [see Use in Specific Populations (8.6) and (8.7)].

Pediatric

TRELSTAR has not been evaluated in patients less than 18 years of age [see Use in Specific Populations (8.4)].

Hepatic and Renal Impairment

After an intravenous bolus injection of 0.5 mg triptorelin, the two distribution half-lives were unaffected by renal and hepatic 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 elimination half-life (see Table 6).  In subjects with hepatic insufficiency, a decrease in triptorelin clearance was more pronounced than that observed with renal insufficiency.  Due to minimal increases in the volume of distribution, the elimination half-life in subjects with hepatic insufficiency was similar to subjects with renal insufficiency.  Subjects with renal or hepatic impairment had 2‑ to 4-fold higher exposure (AUC values) than young healthy males [see Use in Specific Populations (8.6) and (8.7)].

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

In rats, triptorelin doses of 120, 600, and 3000 mcg/kg given every 28 days (approximately 0.3, 2, and 8 times the human monthly dose based on body surface area) resulted in increased mortality with a drug treatment period of 13 – 19 months.  The incidences of benign and malignant pituitary tumors and histiosarcomas were increased in a dose-related manner.  No oncogenic effect was observed in mice administered triptorelin for 18 months at doses up to 6000 mcg/kg every 28 days (approximately 8 times the human monthly dose based on body surface area).

Mutagenicity studies performed with triptorelin using bacterial and mammalian systems (in vitro Ames test and chromosomal aberration test in CHO cells and an in vivo mouse micronucleus test) provided no evidence of mutagenic potential.

After 60 days of subcutaneous treatment followed by a minimum of four estrus cycles prior to mating, triptorelin, at doses of 2, 20, and 200 mcg/kg/day in saline (approximately 0.2, 2, and 16 times the estimated human daily dose based on body surface area) or 2 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.