Trelstar Depot

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Trelstar Depot uses


RECENT MAJOR CHANGES

Warnings and Precautions (5.4) 07/2014

1 INDICATIONS AND USAGE

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

Trelstar Depot is a gonadotropin releasing hormone (GnRH) agonist indicated for the palliative treatment of advanced prostate cancer. (1)

2 DOSAGE AND ADMINISTRATION

Trelstar Depot is administered as a single intramuscular injection in either buttock. Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule.

2.1 Dosing Information

Trelstar Depot must be administered under the supervision of a physician.

Trelstar Depot 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.

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 weeks


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 Depot

Please read the instructions completely before you begin.

2.3 Reconstitution Instructions for Trelstar Depot with MIXJECT SYSTEM

Please read the instructions completely before you begin.

The Trelstar Depot products are sterile, lyophilized biodegradable microgranule formulations supplied as single dose vials. Refer to Table 5 for the composition of each Trelstar Depot product.


Ingredients


Trelstar Depot

3.75 mg


Trelstar Depot

11.25 mg


Trelstar Depot

22.5 mg


Trelstar Depot

(base units)


3.75 mg


11.25 mg


22.5 mg


poly-d,l-lactide-co-glycolide


136 mg


118 mg


182 mg


mannitol, USP


69 mg


76 mg


68 mg


carboxymethylcellulose sodium, USP


24 mg


27 mg


24 mg


polysorbate 80, NF


1.6 mg


1.8 mg


1.6 mg


When 2 mL sterile water is added to the vial containing Trelstar Depot and mixed, a suspension is formed which is intended as an intramuscular injection. Trelstar Depot is available in two packaging configurations: (a) Trelstar Depot vial alone or (b) Trelstar Depot 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.

Structural formula for Trelstar Depot (triptorelin pamoate).

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Triptorelin is a synthetic decapeptide agonist analog of gonadotropin releasing hormone. 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, Trelstar Depot 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 Depot:

Trelstar Depot 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 Depot 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 Depot 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 Depot 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.

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 Depot 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. 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)].


Group


Cmax

(ng/mL)


AUCinf

(h·ng/mL)


Clp

(mL/min)


Clrenal

(mL/min)


t1/2

(h)


Clcreat

(mL/min)


6 healthy male volunteers


48.2

±11.8


36.1

±5.8


211.9

±31.6


90.6

±35.3


2.81

±1.21


149.9

±7.3


6 males with moderate renal impairment


45.6

±20.5


69.9

±24.6


120.0

±45.0


23.3

±17.6


6.56

±1.25


39.7

±22.5


6 males with severe renal impairment


46.5

±14.0


88.0

±18.4


88.6

±19.7


4.3

±2.9


7.65

±1.25


8.9

±6.0


6 males with liver disease


54.1

±5.3


131.9

±18.1


57.8

±8.0


35.9

±5.0


7.58

±1.17


89.9

±15.1

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13 NONCLINICAL TOXICOLOGY

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 Depot 3.75 mg

Trelstar Depot 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 Depot 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 Depot 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 Depot 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 Depot 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 Depot 11.25 mg

Trelstar Depot 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 Depot 11.25 mg (N = 174) every 12 weeks for a total of up to 3 doses (maximum treatment period of 253 days) or Trelstar Depot 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 Depot 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 Depot 11.25 mg.

Trelstar Depot 22.5 mg

Trelstar Depot 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 Depot 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 Depot 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 Depot is provided in Table 7.


Product

Strength


3.75 mg


11.25 mg


22.5 mg


Number of

Patients


137


171


120


Treatment

Schedule


every 4 weeks


every 12 weeks


every 24 weeks


Duration of Study


253 days


253 days


337 days


Castration RateMaintenance of castration was calculated using a frequency distribution.

on Day 29, %

(n/N)


91.2% (125/137)


97.7% (167/171)


97.5% (117/120)


Rate of

Castration

MaintenanceCumulative maintenance of castration was calculated using a survival analysis (Kaplan-Meier) technique.

from Days 57 –

253, %


96.2%


94.4%


not applicable


Rate of

Castration

Maintenance

from Days 57 –

337, % (n/N)


not applicable


not applicable


93.3% (112/120)Calculation includes 5 patients who discontinued the study but who had castrate levels of testosterone prior to discontinuation.

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16 HOW SUPPLIED/STORAGE AND HANDLING

Trelstar Depot is supplied in a single dose vial with a Flip-Off seal containing sterile lyophilized Trelstar Depot microgranules incorporated in a biodegradable copolymer of lactic and glycolic acids.

Trelstar Depot is also supplied in the Trelstar Depot MIXJECT single-dose delivery system consisting of a vial with a Flip-Off seal containing sterile lyophilized Trelstar Depot 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 Depot 3.75 mg – NDC 52544-153-02 (single dose vial) and NDC 52544-189-76 (TRELSTAR 3.75 mg with MIXJECT single-dose delivery system)

Trelstar Depot 11.25 mg – NDC 52544-154-02 (single dose vial) and NDC 52544-188-76 (TRELSTAR 11.25 mg with MIXJECT single-dose delivery system)

Trelstar Depot 22.5 mg – NDC 52544-156-02 (single dose vial) and NDC 52544-092-76 (TRELSTAR 22.5 mg with MIXJECT single-dose delivery system)

Storage

Store at 20-25°C (68-77°F). Do not freeze Trelstar Depot 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:

ACTAVIS

Medical Communications

Parsippany, NJ 07054 USA

1-800-272-5525

Distributed By:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Manufactured By:

Debiopharm Research & Manufacturing SA

CH-1920 Martigny, Switzerland

MIXJECT is manufactured by and is a registered trademark of:

Medimop Medical Projects Ltd.

Ra'anana, Israel

The pre-filled syringe containing sterile water for injection is manufactured by:

Abbott Biologicals BV

Olst, The Netherlands

Content Updated: July 2014



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Trelstar Depot pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Trelstar Depot available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Trelstar Depot destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Trelstar Depot Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Trelstar Depot pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."TRELSTAR (TRIPTORELIN PAMOATE) INJECTION, POWDER, LYOPHILIZED, FOR SUSPENSION TRELSTAR (TRIPTORELIN PAMOATE) KIT [ACTAVIS PHARMA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."TRIPTORELIN PAMOATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "TRIPTORELIN". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Trelstar Depot?

Depending on the reaction of the Trelstar Depot after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Trelstar Depot not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Trelstar Depot addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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