NDC 0023-5906 Trelstar

Triptorelin Pamoate

NDC Product Code 0023-5906

NDC 0023-5906-23

Package Description: 1 KIT in 1 CARTON * 2 mL in 1 VIAL, SINGLE-DOSE * 2 mL in 1 SYRINGE

NDC Product Information

Trelstar with NDC 0023-5906 is a a human prescription drug product labeled by Allergan, Inc.. The generic name of Trelstar is triptorelin pamoate. The product's dosage form is kit and is administered via form.

Labeler Name: Allergan, Inc.

Dosage Form: Kit - A packaged collection of related material.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • MANNITOL (UNII: 3OWL53L36A)
  • CARBOXYMETHYLCELLULOSE SODIUM (UNII: K679OBS311)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • WATER (UNII: 059QF0KO0R)
  • MANNITOL (UNII: 3OWL53L36A)
  • CARBOXYMETHYLCELLULOSE SODIUM (UNII: K679OBS311)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • WATER (UNII: 059QF0KO0R)
  • MANNITOL (UNII: 3OWL53L36A)
  • CARBOXYMETHYLCELLULOSE SODIUM (UNII: K679OBS311)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • WATER (UNII: 059QF0KO0R)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Allergan, Inc.
Labeler Code: 0023
FDA Application Number: NDA022437 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 03-11-2010 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Information for Patients

Triptorelin Injection

Triptorelin Injection is pronounced as (trip'' toe rel' in)

Why is triptorelin injection medication prescribed?
Triptorelin injection is used to treat the symptoms associated with advanced prostate cancer. Triptorelin injection is in a class of medications called gonadotropin-relea...
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Trelstar Product Label Images

Trelstar Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1       Indications And Usage

TRELSTAR is indicated for the palliative treatment of advanced prostate cancer [see Clinical Studies (14)].

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.  Table 1.
     
TRELSTAR Recommended Dosing Dosage 3.75 mg 11.25 mg 22.5 mg Recommended dose 1 injection every 4 weeks 1 injection every 12 weeks 1 injection every 24 weeksDue 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

  • Please read the instructions completely before you begin.Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection.Place the vial in a standing upright position on a clean, flat surface that is covered with a sterile pad or cloth.Remove the Flip-Off® button from the top of the vial, revealing the rubber stopper.Disinfect the rubber stopper with an alcohol wipe.  Discard the alcohol wipe and allow the stopper to dry.Using a syringe fitted with a sterile 21-gauge needle, withdraw 2 mL sterile water for injection, and inject into the vial.Shake well to thoroughly disperse particles to obtain a uniform suspension.  The suspension will appear milky.Slowly withdraw the entire contents of the reconstituted suspension into the syringe.The suspension should be administered immediately after reconstitution.Inject the patient in either buttock with the contents of the syringe.

2.3       Reconstitution Instructions For Trelstar With Mixject System

Please read the instructions completely before you begin.MIXJECT PreparationWash 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.  Remove the Flip-Off button from the top of 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.  Proceed to MIXJECT Activation.MIXJECT ActivationPeel the cover away from the blister pack containing the vial adapter. Do not remove the vial adapter from the blister pack. Place the blister pack containing the vial adapter firmly on the vial top, piercing the vial. Push down gently until you feel it snap in place. Remove the blister pack from the vial adapter.(a) Screw the plunger rod into the barrel end of the syringe. Remove the cap from the syringe barrel. (b) Connect the syringe to the vial adapter byscrewing it clockwise into the opening on the side of the vial adapter. Be sure to gently twist the syringe until it stops turning to ensure a tight connection.While holding the vial, place your thumb on the plunger rod and push the plunger rod in all the way to transfer the diluent from the pre-filled syringe into the vial. Do not release the plunger rod.Keeping the plunger rod depressed, gently swirl the vial so that the diluent rinses the sides of the vial. This will ensure complete mixing of TRELSTAR and the sterile water diluent. The suspension will now have a milky appearance. In order to avoid separation of the suspension, proceed to the next steps without delay.(a) Invert the MIXJECT system so that the vial is at the top.Grasp the MIXJECT system firmly by the syringe and pull back the plunger rod slowly to draw the reconstituted TRELSTAR into the syringe.(b) Return the vial to its upright position, and disconnect the vial adapter and vial from the MIXJECT syringe assembly by turning the plastic cap of the vial adapter clockwise.Grasp only the plastic cap when removing.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. The syringe containing the TRELSTAR suspension is now ready for administration. The suspension should be administered immediately after reconstitution.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. Usethe one-handed technique and activate the mechanism away from yourself and others. Activation of the safety cover causesvirtually no splatter. Immediately discard the syringe assembly after a single use into a suitable sharps container.

3       Dosage Forms And Strengths

Injectable suspension: 3.75 mg, 11.25 mg, 22.5 mg.

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 )].

4.2       Pregnancy

TRELSTAR may cause fetal harm when administered to a pregnant woman.  Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss and fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].  TRELSTAR is contraindicated in women who are or may become pregnant.  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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       Transient Increase In Serum Testosterone

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels.  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 [see Clinical Pharmacology  (12.2)].

5.3       Metastatic Vertebral Lesions And Urinary Tract Obstruction

Cases of spinal cord compression, which may contribute to weakness or paralysis with or without fatal complications, have been reported with GnRH agonists.  If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered.Patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy.

5.4       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.

5.5       Hyperglycemia And Diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.

5.6       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 clinical practice.

5.7       Laboratory Tests

Response to TRELSTAR should be monitored by measuring serum levels of testosterone periodically or as indicated.

5.8       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.

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.Table 2.
     
TRELSTAR 3.75 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reactions*   TRELSTAR 3.75 mgN = 140 N   % Application Site Disorders         Injection site pain 5 3.6  Body as a Whole        Hot flush 82 58.6    Pain 3 2.1    Leg pain 3 2.1    Fatigue 3 2.1  Cardiovascular Disorders         Hypertension 5 3.6  Central and Peripheral Nervous System Disorders         Headache 7 5.0     Dizziness 2 1.4  Gastrointestinal Disorders         Diarrhea 2 1.4     Vomiting 3 2.1  Musculoskeletal System Disorders         Skeletal pain 17 12.1  Psychiatric Disorders         Insomnia 3 2.1     Impotence 10 7.1     Emotional lability 2 1.4  Red Blood Cell Disorders         Anemia 2 1.4  Skin and Appendages Disorders         Pruritus 2 1.4  Urinary System Disorders         Urinary tract infection 2 1.4     Urinary retention 2 1.4 *  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.Table 3.
     
TRELSTAR 11.25 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reactions*  TRELSTAR 11.25 mg N = 174 N %  Application Site      Injection site pain 7 4.0  Body as a Whole      Hot flush 127 73.0    Leg pain 9 5.2    Pain 6 3.4    Back pain 5 2.9    Fatigue 4 2.3    Chest pain 3 1.7    Asthenia 2 1.1    Peripheral edema 2 1.1  Cardiovascular Disorders      Hypertension 7 4.0    Dependent edema 4 2.3  Central and Peripheral Nervous System Disorders      Headache 12 6.9    Dizziness 5 2.9    Leg cramps 3 1.7  Endocrine      Breast pain 4 2.3    Gynecomastia 3 1.7  Gastrointestinal Disorders      Nausea 5 2.9    Constipation 3 1.7    Dyspepsia 3 1.7    Diarrhea 2 1.1    Abdominal pain 2 1.1 Liver and Biliary System      Abnormal hepatic function 2 1.1  Metabolic and Nutritional Disorders      Edema in legs 11 6.3    Increased alkaline phosphatase  3 1.7  Musculoskeletal System Disorders      Skeletal pain 23 13.2    Arthralgia 4 2.3    Myalgia 2 1.1 Psychiatric Disorders      Decreased libido 4 2.3    Impotence 4 2.3    Insomnia 3 1.7    Anorexia 3 1.7  Respiratory System Disorders      Coughing 3 1.7    Dyspnea 2 1.1    Pharyngitis 2 1.1  Skin and Appendages      Rash 3 1.7 Urinary System Disorders      Dysuria 8 4.6    Urinary retention 2 1.1 Vision Disorders      Eye pain 2 1.1    Conjunctivitis 2 1.1*  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. Table 4.
     
TRELSTAR 22.5 mg: Adverse Reactions Reported by 5% or More of Patients During Treatment Adverse Reactions*     TRELSTAR 22.5 mg N = 120 Treatment-Emergent Treatment-Related N  % N % General Disorders and Administration Site Conditions        Edema peripheral 6 5.0 0 0 Infections and Infestations        Influenza 19 15.8 0 0    Bronchitis 6 5.0 0 0 Endocrine        Diabetes Mellitus/Hyperglycemia   6 5.0 0 0 Musculoskeletal and Connective Tissue Disorders        Back pain 13 10.8 1 0.8    Arthralgia 9 7.5 1 0.8    Pain in extremity 9 7.5 1 0.8  Nervous System Disorders        Headache 9 7.5 2 1.7 Psychiatric Disorders        Insomnia 6 5.0 1 0.8 Renal and Urinary Disorders        Urinary tract infection 14 11.6 0 0    Urinary retention 6 5.0 0 0  Reproductive System and Breast Disorders        Erectile dysfunction 12 10.0 12 10.0    Testicular atrophy 9  7.5 9 7.5 Vascular Disorders        Hot flush 87 72.5 86 71.7    Hypertension 17 14.2 1 0.8*  Adverse reactions for TRELSTAR 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA)Changes in Laboratory Values During TreatmentThe 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       Postmarketing 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.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.During postmarketing experience, convulsions, and thromboembolic events including, but not limited to, pulmonary emboli, cerebrovascular accident, myocardial infarction, deep venous thrombosis, transient ischemic attack, and thrombophlebitis have been reported.

7       Drug Interactions

No drug-drug interaction studies involving triptorelin have been conducted.Human pharmacokinetic data with triptorelin suggest that C-terminal fragments produced by tissue degradation are either degraded completely within tissues or are rapidly degraded further in plasma, or cleared by the kidneys. Therefore, hepatic microsomal enzymes are unlikely to be involved in triptorelin metabolism. However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with triptorelin since hyperprolactinemia reduces the number of pituitary GnRH receptors.

8.1       Pregnancy

Pregnancy Category X [see 'Contraindications' section].TRELSTAR is contraindicated in women who are or may become pregnant while receiving the drug.  Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 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).

8.3       Nursing Mothers

TRELSTAR is not indicated for use in women [see Indications and Usage (1)].  It is not known if triptorelin is excreted in human milk.  Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from TRELSTAR, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

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)].

10       Overdosage

There is no experience of overdosage in clinical trials.  In single dose toxicity studies in mice and rats, the subcutaneous LD50 of triptorelin was 400 mg/kg in mice and 250 mg/kg in rats, approximately 500 and 600 times, respectively, the estimated monthly human dose based on body surface area.  If overdosage occurs, therapy should be discontinued immediately and the appropriate supportive and symptomatic treatment administered.

11       Description

TRELSTAR is a white to slightly yellow lyophilized cake.  When reconstituted, TRELSTAR has a milky appearance.  It contains a pamoate salt of triptorelin, a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). The chemical name of triptorelin pamoate is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycine amide (pamoate salt).  The empirical formula is C64H82N18O13 · C23H16O6 and the molecular weight is 1699.9. The structural formula is:Structural formula for TRELSTAR (triptorelin pamoate).The TRELSTAR products are sterile, lyophilized biodegradable microgranule formulations supplied as single dose vials.  Refer to Table 5 for the composition of each TRELSTAR product.Table 5. TRELSTAR Composition  IngredientsTRELSTAR3.75 mgTRELSTAR11.25 mgTRELSTAR22.5 mg  triptorelin pamoate(base units) 3.75 mg11.25 mg22.5 mg  poly-d,l-lactide-co-glycolide138 mg120 mg183 mg  mannitol, USP71 mg74 mg74 mg  carboxymethylcellulose sodium, USP25 mg26 mg26 mg  polysorbate 80, NF1.7 mg1.7 mg1.7 mgWhen 2 mL sterile water is added to the vial containing TRELSTAR and mixed, a suspension is formed which is intended as an intramuscular injection.  TRELSTAR is available in two packaging configurations: (a) TRELSTAR vial alone or (b) TRELSTAR vial plus a MIXJECT vial adapter, and a separate pre-filled syringe that contains sterile water for injection, USP, 2 mL, pH 6 to 8.5.

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.  AbsorptionFollowing 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.DistributionThe 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.MetabolismThe 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.ExcretionTriptorelin 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 PopulationsAge and RaceThe 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)].PediatricTRELSTAR has not been evaluated in patients less than 18 years of age [see Use in Specific Populations (8.4)].Hepatic and Renal ImpairmentAfter 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)].Table 6.
     
Pharmacokinetic Parameters (Mean ± SD) in Healthy Volunteers and Special Populations Following an IV Bolus Injection of 0.5 mg Triptorelin GroupCmax(ng/mL)AUCinf(h·ng/mL)Clp(mL/min)Clrenal(mL/min)t1/2(h)Clcreat(mL/min) 6 healthy male volunteers48.2±11.836.1±5.8211.9±31.690.6±35.32.81±1.21149.9±7.3 6 males with moderate renal impairment45.6±20.569.9±24.6120.0±45.023.3±17.66.56±1.2539.7±22.5 6 males with severe renal impairment46.5±14.088.0±18.488.6±19.74.3±2.97.65±1.258.9±6.0 6 males with liver disease54.1±5.3131.9±18.157.8±8.035.9±5.07.58±1.1789.9±15.1

13.1       Carcinogenesis, Mutagenesis, Impairment Of Fertility

In rats, 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.

14       Clinical Studies

TRELSTAR 3.75 mgTRELSTAR 3.75 mg was studied in a randomized, active control trial of 277 men with advanced prostate cancer.  The clinical trial population consisted of 59.9% Caucasian, 39.3% Black, and 0.8% Other.  There was no difference observed with triptorelin response between racial groups.  Men were between 47 and 89 years of age (mean = 71 years).  Patients received either TRELSTAR 3.75 mg (N = 140) or an approved GnRH agonist monthly for 9 months.  The primary efficacy endpoints were both achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 253.Castration levels of serum testosterone (≤ 1.735 nmol/L; equivalent to 50 ng/dL) in patients treated with TRELSTAR 3.75 mg were achieved at Day 29 in 125 of 137 (91.2%) patients and at Day 57 in 97.7% of patients. Maintenance of castration levels of serum testosterone from Day 57 through Day 253 was found in 96.2% of patients treated with TRELSTAR 3.75 mg.The presence of an acute-on-chronic flare phenomenon was also studied as a secondary efficacy endpoint.  Serum LH levels were measured at 2 hours after repeat TRELSTAR 3.75 mg administration on Days 85 and 169.  One hundred twenty-four of the 126 evaluable patients (98.4%) on Day 85 had a serum LH level of ≤ 1.0 IU/L at 2 hours after dosing, indicating desensitization of the pituitary gonadotroph receptors.TRELSTAR 11.25 mgTRELSTAR 11.25 mg was studied in a randomized, active control trial of 346 men with advanced prostate cancer.  The clinical trial population consisted of 48% Caucasian, 38% Black, and 15% Other.  There was no difference observed with triptorelin response between racial groups.  Men were between 45 and 96 years of age (mean = 71 years).  Patients received either TRELSTAR 11.25 mg (N = 174) every 12 weeks for a total of up to 3 doses (maximum treatment period of 253 days) or TRELSTAR 3.75 mg (N = 172) every 28 days for a total of up to 9 doses.  The primary efficacy endpoints were both achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 253.Castration levels of serum testosterone (≤ 1.735 nmol/L; equivalent to 50 ng/dL) were achieved at Day 29 in 167 of 171 (97.7%) patients treated with TRELSTAR 11.25 mg, and maintenance of castration levels of serum testosterone from Day 57 through Day 253 was found in 94.4% of patients treated with TRELSTAR 11.25 mg.TRELSTAR 22.5 mgTRELSTAR 22.5 mg was studied in a non-comparative trial of 120 men with advanced prostate cancer.  The clinical trial population consisted of 64% Caucasian, 23% Black, and 13% Other, with a mean age of 71.1 years (range 51-93).   Patients received TRELSTAR 22.5 mg (N = 120) every 24 weeks for a total of 2 doses (maximum treatment period of 337 days).  The primary efficacy endpoints included achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 337.Castration levels of serum testosterone (≤ 1.735 nmol/L; equivalent to 50 ng/dL) were achieved at Day 29 in 97.5% (117 of 120) of patients treated with TRELSTAR 22.5 mg. Castration was maintained in 93.3% of patients in the period from Day 57 to Day 337.A summary of the clinical studies for TRELSTAR is provided in Table 7.Table 7.
     
Summary of TRELSTAR Clinical Studies Product Strength3.75 mg11.25 mg22.5 mg Number of Patients137171120 Treatment Scheduleevery 4 weeksevery 12 weeksevery 24 weeks Duration of Study253 days253 days337 days Castration Rate*  on Day 29, % (n/N)91.2% (125/137)97.7% (167/171)97.5% (117/120) Rate of Castration Maintenance† from Days 57 – 253, %96.2%94.4%not applicable Rate of Castration Maintenance from Days 57 – 337, % (n/N)not applicablenot applicable93.3% (112/120)‡*  Maintenance of castration was calculated using a frequency distribution.†  Cumulative maintenance of castration was calculated using a survival analysis (Kaplan-Meier) technique.‡  Calculation includes 5 patients who discontinued the study but who had castrate levels of testosterone prior to discontinuation.

16       How Supplied/Storage And Handling

TRELSTAR is supplied in the TRELSTAR MIXJECT single-dose delivery system consisting of a vial with a Flip-Off seal containing sterile lyophilized triptorelin pamoate microgranules incorporated in a biodegradable copolymer of lactic and glycolic acids, a MIXJECT vial adapter, and a pre-filled syringe containing sterile water for injection, USP, 2 mL, pH 6 to 8.5.TRELSTAR 3.75 mg –NDC 0023-5902-04 (TRELSTAR 3.75 mg with MIXJECT single-dose delivery system)TRELSTAR 11.25 mg –NDC 0023-5904-12 (TRELSTAR 11.25 mg with MIXJECT single-dose delivery system)TRELSTAR 22.5 mg –NDC 0023-5906-23 (TRELSTAR 22.5 mg with MIXJECT single-dose delivery system)StorageStore at 20-25°C (68-77°F).  [See USP Controlled Room Temperature.]  Do not freeze TRELSTAR with MIXJECT.

17       Patient Counseling Information

Instruct patients that they will likely experience an increase in serum testosterone levels following their initial injection. This may cause a worsening of their symptoms of prostate cancer during the first weeks of treatment. These symptoms may include bone pain, spinal cord injury, hematuria, and urethral or bladder outlet obstruction. This increase in serum testosterone levels and associated symptoms should decline 3 to 4 weeks following their injection. Use of drugs appropriate for alleviating the risk associated with the increase should be discussed with patients prior to administration of the products. Patients should also be informed about the increased risk of developing diabetes, myocardial infarction, sudden cardiac death and stroke in men in association with use of GnRH agonists.Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment.  Patients should report any previous hypersensitivity reactions to triptorelin, or other GnRH agonists, or GnRH.For all medical inquiries contact:AllerganMedical Communications1-800-678-1605Distributed By:Allergan USA, Inc.Irvine, CA 92612Manufactured By:Debiopharm Research & Manufacturing SACH-1920 Martigny, SwitzerlandMIXJECT is manufactured by and is a registered trademark of:Medimop Medical Projects Ltd.Ra'anana, IsraelThe pre-filled syringe containing sterile water for injection is manufactured by:Baxter Pharmaceutical Solutions, LLC 927 South Curry Pike Bloomington, Indiana 47403TRELSTAR® and its design are registered trademarks of Allergan Sales, LLCMIXJECT® is a registered trademark of Medimop Medical Projects Ltd.© 2018 Allergan. All rights reserved.73175US12

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