Pr TRELSTARTM (1 month slow-release) Triptorelin Pamoate for Injectable Suspension Microgranules for depot suspension 3.75 mg triptorelin (as pamoate) per vial (1 month slow release) with single dose delivery system and Sterile Water for Injection (2mL) 3.75 mg triptorelin (as pamoate) per vial (1 month slow release) without Sterile Water for Injection (2mL)
Pr TRELSTARTM LA (3 month slow-release) Triptorelin Pamoate for Injectable Suspension Microgranules for depot suspension 11.25 mg triptorelin per vial (3 month slow release) with single dose delivery system and Sterile Water for Injection (2mL) 11.25 mg triptorelin per vial (3 month slow release) without Sterile Water for Injection (2mL)
Watson Laboratories, Inc. Date of Revision: August 27, 2008 311 Bonnie Circle Corona, CA, USA, 92880 Distributed by: Paladin Labs Inc. Control No. 120938 Montreal, QC H4P 2T4 Trelstar is a trademark of Watson Laboratories Inc.
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 15 ACTION AND CLINICAL PHARMACOLOGY 16 STORAGE AND STABILITY 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 18
PHARMACEUTICAL INFORMATION 20 CLINICAL TRIALS 20 DETAILED PHARMACOLOGY 23 TOXICOLOGY 24 REFERENCES 26
Pr TRELSTARTM (1 month slow-release) Pr TRELSTARTM LA (3 month slow-release) Triptorelin Pamoate for Injectable Suspension | ||
|---|---|---|
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intramuscular | Powder (microgranules) for slow release suspension 3.75 mg of triptorelin peptide base units/vial; 11.25 mg of triptorelin peptide base units/vial | For a complete listing see Dosage Forms, Composition and Packaging section. |
TRELSTAR and TRELSTAR LA (triptorelin pamoate for injectable suspension) are indicated for: the palliative treatment of hormone dependent advanced carcinoma of the prostate gland (stage D2).
Geriatrics (>65 years of age):
The majority of the patients studied in the clinical trials for TRELSTAR and TRELSTAR LA were 65 years and older (see CLINICAL TRIALS).
Pediatrics (<18 years of age):
The safety and effectiveness of TRELSTAR and TRELSTAR LA in pediatric patients have not been established (see WARNINGS AND PRECAUTIONS).
TRELSTAR and TRELSTAR LA must be administered under the supervision of a physician.
TRELSTAR and TRELSTAR LA are contraindicated in patients with hypersensitivity to gonadotropin releasing hormone or luteinizing hormone-releasing hormone (GnRH or LHRH), GnRH agonist analogs or any ingredient in the formulation or component of the container. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported (see WARNINGS AND PRECAUTIONS). For a complete listing, see the Dosage Forms, Composition and Packaging sections of the Product Monograph. TRELSTAR and TRELSTAR LA are contraindicated in women who are or may become pregnant while receiving the drug. TRELSTAR and TRELSTAR LA may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus (See WARNINGS AND PRECAUTIONS section). TRELSTAR and TRELSTAR LA are contraindicated in nursing women (See WARNINGS AND PRECAUTIONS section).
General
TRELSTAR and TRELSTAR LA (triptorelin pamoate for injection), like other LH-RH agonists, cause a transient increase in serum concentration of testosterone during the first weeks of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction. Cases of spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LH-RH agonists. If spinal cord compression or renal impairment due to ureteral obstruction develops, standard treatment of these complications should be instituted. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should begin triptorelin therapy under close supervision. Hypersensitivity and anaphylactic reactions have been reported with triptorelin as with other LHRH agonists (see Post-Market Adverse Drug Reactions).
Carcinogenesis and Mutagenesis
Carcinogenicity and mutagenicity studies have been performed in animals (see TOXICOLOGY section).
Endocrine and Metabolism
Bone loss can be expected as part of natural aging and can also be anticipated during the hypoandrogenic state caused by long-term use of triptorelin. In patients with significant risk factors for decreased bone mineral content and/or bone mass such as family history of osteoporosis, chronic use of corticosteroids or anticonvulsants or chronic abuse of alcohol or tobacco, triptorelin may pose additional risk. In these patients, risk versus benefit must be weighed carefully before initiation of triptorelin therapy.
Long-term administration of triptorelin will cause suppression of pituitary gonadotropins and gonadal hormone production with clinical symptoms of hypogonadism. These changes have been observed to reverse on discontinuation of therapy. However, whether the clinical symptoms of induced hypogonadism will reverse in all patients has not yet been established. In prostate cancer patients, an assessment of bone lesions may require the use of bone scans. Prostatic lesions may be monitored by ultrasonography/or CT scan in addition to digital rectal examination. The status of obstructive uropathy may be assessed and/or diagnosed using intravenous pyelography, ultrasonography or CT scan.
Renal and Hepatic
Triptorelin exposure was higher in patients with renal or hepatic insufficiency than in healthy volunteers. Clinical consequences of the increase and potential need for dose adjustment are unknown.
Special Populations
The safe use of triptorelin during pregnancy has not been established clinically. If a woman becomes pregnant while receiving TRELSTAR or TRELSTAR LA, therapy should be discontinued and the patient advised of the potential risk to the fetus. The possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy (See CONTRAINDICATIONS section).
It is not known to what extent triptorelin is excreted into human milk and caution should be exercised when TRELSTAR or TRELSTAR LA is administered to nursing women. (See CONTRAINDICATIONS section)
The majority of the patients studied in the clinical trials for TRELSTAR and TRELSTAR LA were 65 years and older.
The safety and effectiveness of TRELSTAR and TRELSTAR LA in pediatric patients have not been established.
The effects of race on triptorelin pharmacokinetics, safety, and efficacy have not been systematically studied. In the three controlled clinical studies conducted to compare a controlled release formulation of triptorelin acetate with orchiectomy, no race data were collected. The study that compared TRELSTAR (1-month, 3.75 mg triptorelin pamoate formulation) and TRELSTAR LA (3-month, 11.25 mg triptorelin pamoate formulation), included
47.7% Caucasian, 37.6% Black, and 14.7% Colored patients.
Monitoring and Laboratory Tests
During therapy with TRELSTAR and TRELSTAR LA, patients should be routinely monitored by physical examinations and appropriate laboratory tests. Response to TRELSTAR and TRELSTAR LA may be monitored by periodically measuring serum concentrations of testosterone and prostate specific antigen. Results of testosterone determinations are dependant on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.
Adverse Drug Reaction Overview
Triptorelin pamoate has been found to be generally well tolerated in clinical trials. Adverse reactions reported in these trials were rarely severe enough to result in patient withdrawal from triptorelin treatment. Three postmarketing reports of anaphylactic shock and seven postmarketing reports of angioedema related to triptorelin administration have been reported since 1986 (see WARNINGS AND PRECAUTIONS). In clinical trials, no serious adverse events that were considered to be related to study drug administration were reported. As seen with other LHRH agonist therapies, the most commonly observed adverse events during triptorelin treatment were due to the expected physiological effects related to decreased testosterone levels. These effects included hot flushes, impotence, and decreased libido. TRELSTAR and TRELSTAR LA, like other LH-RH analogs, caused a transient increase in serum testosterone concentrations during the first weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms (see WARNINGS AND PRECAUTIONS).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Clinical Studies with Triptorelin Acetate
Three controlled clinical studies were conducted on 265 patients to compare a controlled release formulation of triptorelin acetate (N=160) with orchiectomy (N=105). In the first study, all patients received an i.m. injection of 3.75 mg triptorelin and every month thereafter for 24 months, with the exception of 3 patients who received 100 ug triptorelin s.c. for the first month. In the second study, all patients received 100 ug triptorelin s.c. for the first 7 days, and 3.75 mg i.m. on Days 8, 28, and every month thereafter for up to 18 months. In the third study, all patients received an i.m. injection of 3.75 mg triptorelin on Days 0 and 28, and every month thereafter for 24 months. In these studies, the most commonly observed adverse events reported in 5% or more of patients were: impotence (50.0% in the triptorelin group and 41.2% in the orchiectomy group), decreased libido (44.9% of patients in the triptorelin group and 39.2% in the orchiectomy group), hot flushes (44.9% in the triptorelin group and 43.3% in the orchiectomy group) and reduced size of genitalia (12.2% in the triptorelin group). These events are known to be related to biochemical or surgical castration. (See CLINICAL TRIALS)
Clinical Study with Triptorelin Pamoate
The safety of triptorelin was also evaluated in a study that compared TRELSTAR (1-month, 3.75 mg triptorelin pamoate formulation) and TRELSTAR LA (3-month, 11.25 mg triptorelin pamoate formulation). The patients in this study were randomized to receive either three injections of triptorelin pamoate 3-month formulation (11.25 mg), administered i.m. every 84 days for 9 months, or nine injections of triptorelin pamoate 1-month formulation (3.75 mg), administered i.m. every 28 days for 9 months. The following possibly or probably related systemic adverse events were reported by 1% or more of patients in this study:
| TABLE 1. INCIDENCE (%) OF POSSIBLY OR PROBABLY RELATED SYSTEMIC ADVERSE EVENTS REPORTED BY 1% OR MORE OF PATIENTS IN EITHER TREATMENT GROUP TREATED WITH TRELSTAR 3.75 MG (1 INJECTION EVERY 28 DAYS FOR 9 MONTHS) AND TRELSTAR LA (1 INJECTION EVERY 84 DAYS FOR 9 MONTHS) | ||
| TRELSTAR (3.75 mg) N = 172 n (%) | TRELSTAR LA (11.25 mg) N=174 n (%) | |
| Application Site Disorders Injection site pain | 2 (1.2) | 7 (4.0) |
| Body as a Whole | 114 (66.3) | 127 (73.0) |
| Hot flushes * | ||
| Back pain | 6 (3.5) | 5 (2.9) |
| Pain | 10 (5.8) | 6 (3.4) |
| Leg pain | 5 (2.9) | 9 (5.2) |
| Fatigue | 5 (2.9) | 4 (2.3) |
| Chest pain | 0 (0.0) | 3 (1.7) |
| Asthenia | 2 (1.2) | 2 (1.1) |
| Oedema peripheral | 3 (1.7) | 2 (1.1) |
| Allergic reaction | 2 (1.2) | 0 (0.0) |
| Cardiovascular Disorders | 8 (4.7) | 7 (4.0) |
| Hypertension | ||
| Oedema dependant | 0 (0.0) | 4 (2.3) |
| Central and Peripheral Nervous System | 7 (4.1) | 12 (6.9) |
| Disorders | ||
| Headache | ||
| Dizziness | 5 (2.9) | 5 (2.9) |
| Cramps legs | 1 (0.6) | 3 (1.7) |
| Endocrine Disorders | 5 (2.9) | 4 (2.3) |
| Breast pain male | ||
| Gynecomastia | 0 (0.0) | 3 (1.7) |
| Gastro-intestinal System Disorders | 4 (2.3) | 3 (1.7) |
| Constipation | ||
| Nausea | 7 (4.1) | 5 (2.9) |
| Diarrhoea | 4 (2.3) | 2 (1.1) |
| Abdominal pain | 1 (0.6) | 2 (1.1) |
| Dyspepsia | 2 (1.2) | 3 (1.7) |
Expected pharmacological consequence of testosterone suppression (Continued)
| TABLE 1. INCIDENCE (%) OF POSSIBLY OR PROBABLY RELATED SYSTEMIC ADVERSE EVENTS REPORTED BY 1% OR MORE OF PATIENTS IN EITHER TREATMENT GROUP TREATED WITH TRELSTAR 3.75 MG (1 INJECTION EVERY 28 DAYS FOR 9 MONTHS) AND TRELSTAR LA (1 INJECTION EVERY 84 DAYS FOR 9 MONTHS) (CONTINUED) | ||
| TRELSTAR (3.75 mg) N = 172 n (%) | TRELSTAR LA (11.25 mg) N=174 n (%) | |
| Heart Rate and Rhythm Disorders Palpitation | 3 (1.7) | 0 (0.0) |
| Liver and Biliary System Disorders Hepatic function abnormal | 0 (0.0) | 2 (1.1) |
| Metabolic and Nutritional Disorders | 14 (8.1) | 11 (6.3) |
| Oedema legs | ||
| Diabetes mellitus | 2 (1.2) | 1 (0.6) |
| Musculo-skeletal Disorders | 20 (11.6) | 23 (13.2) |
| Skeletal pain | ||
| Arthralgia | 4 (2.3) | 4 (2.3) |
| Myalgia | 1 (0.6) | 2 (1.1) |
| Psychiatric Disorders | 2 (1.2) | 3 (1.7) |
| Insomnia | ||
| Depression * | 3 (1.7) | 1 (0.6) |
| Impotence * | 7 (4.1) | 4 (2.3) |
| Anorexia | 1 (0.6) | 3 (1.7) |
| Libido decreased * | 1 (0.6) | 4 (2.3) |
| Respiratory System Disorders | 1 (0.6) | 3 (1.7) |
| Coughing | ||
| Dyspnoea | 3 (1.7) | 2 (1.1) |
| Pharyngitis | 0 (0.0) | 2 (1.1) |
| Skin and Appendages Disorders | 1 (0.6) | 3 (1.7) |
| Rash | ||
| Pruritus | 2 (1.2) | 0 (0.0) |
| Urinary System Disorders | 3 (1.7) | 0 (0.0) |
| Urinary tract infection | ||
| Dysuria | 3 (1.7) | 8 (4.6) |
| Urinary retention | 0 (0.0) | 2 (1.1) |
| Vision Disorders | 1 (0.6) | 2 (1.1) |
| Eye pain | ||
| Conjuncitivitis | 0 (0.0) | 2 (1.1) |
Expected pharmacological consequence of testosterone suppression
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Adverse drug reactions that were reported by 1% or less of subjects in both the TRELSTAR 3.75 mg and TRELSTAR LA 11.25 mg treatment groups, and were considered to be possibly or probably related to study drug, included the following: injection site reaction, malaise, muscle weakness, rhinitis, skin disorder, and hematuria.
Abnormal Hematologic and Clinical Chemistry Findings
The incidence rate greater than 15% for low abnormal laboratory values (hemoglobin and erythrocyte count) and high abnormal laboratory values (fasting glucose, BUN, and alkaline phosphatase) were comparable for both TRELSTAR and TRELSTAR LA.
Post-Market Adverse Drug Reactions
During post-marketing surveillance, three cases of anaphylatic shock and two cases of angioedema have been reported that were related to triptorelin.
Overview
No formal drug interaction studies have been conducted with TRELSTAR and no data are available on the interaction with alcohol. In the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be prescribed concomitantly with triptorelin pamoate since hyperprolactinemia reduces the number of pituitary GnRH receptors.
Drug-Drug Interactions
Interactions with other drugs have not been established.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Administration of LHRH analogs, including triptorelin, in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Diagnostic tests of pituitary-gonadal function conducted during treatment and within 4 to 12 weeks after discontinuation of therapy with a LHRH agonist may therefore be misleading.
Recommended Dose and Dosage Adjustment
Triptorelin pamoate is intended for long-term administration unless clinically inappropriate.
The recommended dose of TRELSTAR (triptorelin for injectable suspension) is 3.75 mg (as peptide base) incorporated in a depot formulation, monthly. The lyophilized microgranules are to be reconstituted either with
2 mL of sterile water for injection utilizing a 21-gauge needle or using one of the single dose delivery systems (Clip'n'Ject(r) or MIXJECTTM). Administer monthly as a single intramuscular injection, in accordance with the Instructions for use (see below). TRELSTAR LA (3 month slow release) 11.25 mg triptorelin/vial: The recommended dose of TRELSTAR LA (triptorelin for injectable suspension) is 11.25 mg (as peptide base), incorporated in a depot formulation, every 3 months. The lyophilized microgranules are to be reconstituted either with 2 mL of sterile water for injection utilizing a 21-gauge needle or using one of the single dose delivery systems (Clip'n'Ject(r) or MIXJECTTM). Administer every 3 months as a single intramuscular injection, in accordance with the Instructions for use (see below).
Administration
TRELSTAR and TRELSTAR LA are administered as a single intramuscular injection.
Missed Dose
Maintaining testosterone suppression is important in treating the symptoms of hormone- dependent prostate cancer. Missing an appointment by a few days should not disrupt the benefits of treatment, but keeping a consistent schedule of TRELSTAR and TRELSTAR LA injections is an important part of treatment.
Reconstitution
TRELSTAR and TRELSTAR LA are supplied in single-dose vials containing lyophilized microgranules. These microgranules are to be reconstituted with 2 mL of sterile water for injection. Instructions are provided (see below) for reconstitution using the TRELSTAR and TRELSTAR LA dose delivery system (with Sterile Water for Injection), Clip'n'Ject(r); the TRELSTAR and TRELSTAR LA dose delivery system (with Sterile Water for Injection), MIXJECTTM and the TRELSTAR and TRELSTAR LA vial (without Sterile Water for Injection). When 2 mL of Sterile Water for Injection is added to the lyophilized triptorelin pamoate microgranules and mixed, a suspension is formed. For TRELSTAR (1 month slow release) this is equivalent to 3.75 mg of triptorelin peptide base units intended as a single monthly intramuscular injection. For TRELSTAR LA (3 month slow release) this is equivalent to 11.25 mg of triptorelin peptide base units intended as a single 3 month intramuscular injection. The suspension should be discarded if not used immediately after reconstitution. As with other drugs administered by intramuscular injection, the injection site should be varied periodically. As with all parenteral admixtures, the reconstituted product should be examined for the presence of foreign particulate matter, agglomeration or discoloration. Any defective units should be discarded. Single use only. Inject immediately after reconstitution and discard unused portion.
Instructions for Use - TRELSTAR and TRELSTAR LA Dose Delivery System (with Sterile Water for Injection), Clip'n'Ject (r): Please read complete instructions before you begin.
Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection. Place the package containing the Clip'n'Ject system and the Trelstar(r) vial on a clean, flat surface that is covered with a sterile pad or cloth. Peel the Tyvek(r) cover away from the blister package, and place the vial, connector, alcohol swab, and plunger rod on the prepared surface. Be sure to begin by removing the Flip-Off(r) button from the top of the vial, revealing the rubber stopper. Disinfect the rubber portion of the vial cap with the alcohol swab. Discard the alcohol swab and let the alcohol dry. Proceed to Clip'n'Ject Activation.
After administering Trelstar(r) or Trelstar(r) LA, dispose of the Clip'n'Ject system as follows: Place Clip'n'Ject with attached vial in standing upright position on a flat surface. Using one hand, replace the syringe into the Clip'n'Ject connector. Dispose of syringe and attached Clip'n'Ject connector with vial into a suitable sharps container.
FLIP-OFF(r) BUTTON
PLUNGER
NEEDLE
SHIELD
SYRINGE BARREL
VIAL ADAPTER
SAFETY COVER
VIAL
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 MIXJECTTM components and the TRELSTAR(r) vial. Remove the Flip-Off(r) 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 MIXJECTTM Activation.
1.
Peel 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.
4.
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(r) 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.
2a.
2b.
Screw the plunger rod into the barrel end of the syringe. Remove the cap from the syringe barrel.
Connect the syringe to the vial adapter by screwing 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.
5a.
5b.
Invert the MIXJECT(r) system so that the vial is at the top. Grasp the MIXJECT(r) system firmly by the syringe and pull back the plunger rod slowly to draw the reconstituted TRELSTAR(r) into the syringe.
Return the vial to its upright position, and disconnect the vial adapter and vial from the MIXJECT(r) syringe assembly by turning the plastic cap of the vial adapter clockwise. Grasp only the plastic cap when removing.
6.
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.
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(r) suspension is now ready for administration. The suspension should
be administered immediately after reconstitution.
MIXJECT(r) Disposal
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. Use the one-handed technique and activate the mechanism away from yourself and others. Activation of the safety cover causes virtually no splatter.
Immediately discard the syringe assembly after a single use into a suitable sharps container.
.
The lyophilized microgranules are to be reconstituted in sterile water. No other diluent should be used. It is necessary for an aseptic technique to be maintained throughout preparation.
Using a syringe fitted with a sterile 21-gauge needle, withdraw 2 mL sterile water for injection, USP, and after removing the flip-off seal from the vial, inject into the vial.
Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.
Withdraw the entire content of the reconstituted suspension into the syringe and inject it immediately.
Dispose of the syringe and vial into a suitable sharps container.
The pharmacologic properties of triptorelin pamoate and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Acute animal toxicity of the drug is low and high multiples of clinical dose did not cause any adverse effects. If overdosage occurs, it should be managed symptomatically.
Triptorelin is a synthetic decapeptide agonist analog of naturally occurring luteinizing hormone- releasing hormone (LHRH), also called gonadotropin releasing hormone (GnRH). This analog possesses greater potency than the natural hormone. Triptorelin, a LHRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. On administration of triptorelin there is an initial and transient increase in circulating levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone. However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular steroidogenesis. A reduction of serum testosterone levels into the range normally seen in surgically castrated men occurs approximately 2 to 4 weeks after initiation of therapy. This results in accessory sexual organ atrophy which is generally reversible upon discontinuation of drug therapy. Following a single intramuscular injection of TRELSTAR (triptorelin pamoate for injectable suspension) as a 1 month sustained release formulation to healthy male volunteers, serum testosterone levels first increased, peaking on day 4, and thereafter declined to low levels by 4 weeks. By week 8, following this single injection, low levels of testosterone were no longer maintained. A similar serum testosterone profile was observed in patients with advanced prostate cancer after intramuscular injection. Following intramuscular injection of TRELSTAR LA (triptorelin pamoate for injectable suspension) in patients with advanced prostate cancer, serum testosterone levels first increased, peaking around day 2, and thereafter declined to low levels by 4 weeks. This suppression of testosterone, similar to castrate levels (<50 ng/dL), was maintained for 3 months after the first injection and on repeat administration. Intramuscular injection of TRELSTAR LA every 3 months ensures that exposure to triptorelin is maintained with no clinically significant accumulation.
Pharmacokinetics
Triptorelin is not active when given orally. The pharmacokinetic parameters following single intramuscular injections of triptorelin 3.75 mg and 11.25 mg sustained release formulations are listed in Table 2. The plasma concentrations for the 3.75 mg formulation declined to 0.084 ng/mL at 4 weeks.
| TABLE 2. PHARMACOKINETIC PARAMETERS OF TRIPTORELIN (mean +- SD or median (range) for T m ax ) | ||||
| Triptorelin Pharmacokinetics | ||||
| Dose No. of Subjects | C max (ng/mL) | T max (h) | F (%) * (No. of days) | |
| AUC (h *ng/mL) | ||||
| 3.75 mg 20 healthy male volunteers | 28.43 +- 7.31 | 1.0 (1.0 - 3.0) | 223.15 +- 46.96 a | 83 (28 d) |
| 11.25 mg 13 prostate cancer patients | 38.5 +- 10.5 | 2.0 (2.0 - 4.0) | 2268.0 +- 444.63 b | 103 (85 d) |
Computed as the mean AUC of the study divided by the mean AUC of healthy volunteers corrected for dose (AUC = 36.1 h *ng/mL; 500 mg IV bolus of triptorelin).
a AUC (0-28 d), b AUC (0-85 d)
The volume of distribution of triptorelin following IV administration of 0.5 mg triptorelin was approximately 30L in healthy male volunteers. Since there is no evidence that triptorelin at clinically relevant concentrations binds to plasma proteins, drug interactions involving binding-site displacement are unlikely (see DRUG INTERACTIONS).
Metabolites of triptorelin have not been determined in humans. However, human pharmacokinetic data suggest that C-terminal fragments produced by degradation are either completely degraded within tissues or are rapidly further degraded in plasma, or cleared by the kidneys.
Excretion: Triptorelin is eliminated by both the liver and the kidneys. Following IV administration of 0.5 mg triptorelin peptide to 6 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 non-renal clearance of triptorelin (patient anuric, Clcreat=0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependant on the liver (see Special Populations).
Renal and Hepatic Impairment
: After an IV injection of 0.5 mg triptorelin peptide, the two distribution half-lives were unaffected by renal and hepatic impairment, but renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as an increase in volume of distribution and consequently an increase in elimination half- life (Table 3). The decrease in triptorelin clearance was more pronounced in subjects with liver insufficiency, but the half-life was prolonged similarly in subjects with renal insufficiency, since the volume of distribution was only minimally increased.
| TABLE 3. PHARMACOKINETIC PARAMETERS (MEAN +- SD) IN HEALTHY VOLUNTEERS AND SPECIAL POPULATIONS | ||||||||
| Group | C max (ng/mL) | AUC inf (h *ng/mL) | Cl p (mL/min) | C l renal (mL/min) | T 1/2 (h) | C l creat (mL/min) | ||
| 6 healthy male | 48.2 | 36.1 | 211.9 | 90.6 | 2.81 | 149.9 | ||
| volunteers | +-11.8 | +-5.8 | +-31.6 | +-35.3 | +-1.21 | +-7.3 | ||
| 6 males with moderate | 45.6 | 69.9 | 120.0 | 23.3 | 6.56 | 39.7 | ||
| renal impairment | +-20.5 | +-24.6 | +-45.0 | +-17.6 | +-1.25 | +-22.5 | ||
| 6 males with severe | 46.5 | 88.0 | 88.6 | 4.3 | 7.65 | 8.9 | ||
| renal impairment | +-14.0 | +-18.4 | +-19.7 | +-2.9 | +-1.25 | +-6.0 | ||
| 6 males with liver | 54.1 | 131.9 | 57.8 | 35.9 | 7.58 | 89.9 | ||
| disease | +-5.3 | +-18.1 | +-8.0 | +-5.0 | +-1.17 | +-15.1 | ||
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 250 mL/min) indicates that triptorelin was eliminated twice as fast in this young population (see Special Populations, Renal and Hepatic Impairment) as compared to 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.
Store TRELSTAR and TRELSTAR LA vial supplied with Clip'n'Ject(r) Dose Delivery System (with Sterile Water for Injection) at 20 - 25 degC (68 - 77 degF); excursions permitted: 15 - 30 degC (59 - 86 degF). Store TRELSTAR and TRELSTAR LA vial supplied with MIXJECTTM Dose Delivery System (with Sterile Water for Injection) at 20 - 25 degC (68 - 77 degF); excursions permitted: 15 - 30 degC (59 - 86 degF). Store TRELSTAR and TRELSTAR LA vial (without Sterile Water for Injection) at 4 - 25 degC (39 - 77 degF). No refrigeration necessary. Protect from freezing. Protect from light. Unused portion of reconstituted TRELSTAR and TRELSTAR LA should be discarded immediately.
TRELSTAR (1 month slow release) 3.75 mg triptorelin/vial
TRELSTAR is supplied in a vial containing sterile lyophilized triptorelin pamoate microgranules which are equivalent to 3.75 mg triptorelin peptide base, poly-d,l-lactide-co-glycolide (170 mg), mannitol, USP (85 mg), carboxymethylcellulose sodium, USP (30 mg), and polysorbate 80, USP (2 mg). When 2 mL Sterile Water for Injection is added to the microgranules and mixed, a suspension is formed, which is intended as a single, monthly intramuscular injection.
TRELSTAR LA (3 month slow release) 11.25 mg triptorelin/vial
TRELSTAR LA is supplied in a vial containing sterile lyophilized triptorelin pamoate microgranules which are equivalent to 11.25 mg triptorelin peptide base, poly-d,l-lactide-co- glycolide (145 mg), mannitol, USP (85 mg), carboxymethylcellulose sodium, USP (30 mg), and polysorbate 80, USP (2 mg). When 2 mL Sterile Water for Injection is added to the microgranules and mixed, a suspension is formed, which is intended as a single, 3 month intramuscular injection. TRELSTAR and TRELSTAR LA are available in three presentations:
: The accompanying pre-filled syringe contains 2 mL Sterile Water for Injection.
: The accompanying pre-filled syringe contains 2 mL Sterile Water for Injection.