Trelstar 3.75 mg: Indications, Dosage, Precautions, Adverse Effects
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Trelstar 3.75 mg - Product Information

Manufacture: Actavis
Country: Canada
Condition: Prostate Cancer
Class: Gonadotropin releasing hormones, Hormones/antineoplastics
Form: Intramuscular (IM), Powder
Ingredients: Triptorelin Pamoate, Poly-d,l-lactide-co-glycolide, Mannitol, Carboxymethylcellulose Sodium and Polysorbate 80

Summary product information

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 For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and clinical use

TRELSTAR (triptorelin for injectable suspension) is indicated for:

  • The management and relief of chronic pain associated with endometriosis.

TRELSTAR must be administered under the supervision of a physician.

Experience in women has been limited to women 18 years of age or older treated for 6 months.

Geriatrics (> 65 years of age)

No data are available.

Pediatrics (< 18 years of age)

Safety and effectiveness of TRELSTAR in women with endometriosis under the age of 18 years have not been established.

Contraindications

  • TRELSTAR is 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 and Post-Market Adverse Drug Reactions sections). For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • TRELSTAR is contraindicated in women who are or may become pregnant while receiving the drug. TRELSTAR 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 is contraindicated in nursing women (see WARNINGS AND PRECAUTIONS section).
  • TRELSTAR is contraindicated in women with undiagnosed abnormal vaginal bleeding.

Warnings and precautions

General

During the early phase of therapy, sex hormones usually rise above baseline levels because of the physiologic effect of the drug. An increase in clinical signs and symptoms of endometriosis is often observed during the initial days of therapy. These will subside with continued treatment.

Worsening of the clinical condition may occasionally require discontinuation of therapy.

Hypersensitivity and anaphylactic reactions have been reported with triptorelin as with other LHRH agonists. TRELSTAR should not be administered to individuals who are hypersensitive to triptorelin, other LHRH agonists, or LHRH (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions section). In the event of a hypersensitivity reaction, TRELSTAR therapy should be discontinued immediately and the appropriate supportive and symptomatic care should be administered.

Before initiating treatment with TRELSTAR, pregnancy must be ruled out (see Special Populations – Pregnant Women section).

Retreatment cannot be recommended since safety data beyond 6 months are not available.

Carcinogenesis and Mutagenesis

Carcinogenicity and mutagenicity studies have been performed in animals (see TOXICOLOGY section).

Endocrine and Metabolism

Changes in Bone Mineral Density

Bone loss can be expected as part of natural aging and can also be anticipated during the hypoestrogenic state caused by long-term use of triptorelin. Some of the bone density loss over the course of triptorelin therapy may not be reversible. For a period up to 6 months, this bone loss should not be important.

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 use of alcohol or tobacco, triptorelin may pose additional risk. In these patients, risk versus benefit must be weighted carefully before initiation of triptorelin therapy. Repeated courses of therapy with gonadotropin-releasing hormone analogs beyond 6 months are not advisable for patients with major risk factors for loss of bone mineral content.

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.

Genitourinary

Vaginal Bleeding

Since menstruation should stop with effective doses of TRELSTAR, the patient should notify her physician if regular menstruation persists. Patients missing successive doses of TRELSTAR may experience breakthrough bleeding.

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.

Sexual Function/Reproduction

Ovarian Cysts

As with other drugs that stimulate the release of gonadotropin or that induce ovulation, ovarian cysts have been reported to occur, usually within thpe first 2 months of treatment. In most cases, these enlargements resolve spontaneously in 4 to 6 weeks. However, in some cases they may require discontinuation of drug and/or surgical intervention.

Special Populations

Pregnant Women

The safe use of triptorelin during pregnancy has not been established clinically (see Adverse Reactions section). Before starting therapy with TRELSTAR, pregnancy must be excluded. When used regularly and at therapeutic doses, TRELSTAR inhibits ovulation and subsequently menstruation. However, contraception cannot be insured. Women should use nonhormonal methods of contraception while on therapy and should be advised to see their physician if they think they may be pregnant. If a woman becomes pregnant while receiving TRELSTAR, 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.

Nursing Women

It is not known to what extent TRELSTAR is excreted into human milk. Because there are no well-controlled studies on the effect of TRELSTAR in nursing women and because many drugs are excreted into human milk, caution should be exercised when TRELSTAR is administered to nursing women (see CONTRAINDICATIONS section).

Pediatrics (< 18 years of age)

Safety and effectiveness of TRELSTAR in women with endometriosis under the age of 18 years have not been established.

Race

The effects of race on triptorelin pharmacokinetics, safety, and efficacy have not been systematically studied. The controlled study comparing triptorelin [3.75 mg] and leuprolide [3.75 mg] administered monthly for 6 months to endometriosis patients included 97.1% Caucasian, 2.2% Asian, and 0.7% Afro-Caribbean patients.

Monitoring and Laboratory Tests

Before starting therapy with TRELSTAR, pregnancy must be excluded.

Adverse reactions

Adverse Drug Reaction Overview

Triptorelin 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 section). In a controlled study comparing triptorelin [3.75 mg] and leuprolide [3.75 mg] administered monthly for 6 months to endometriosis patients, one case of severe acute abdominal pain was judged probably related to therapy.

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 hypoestrogenism. These effects included hot flushes, vaginal dryness, and amenorrhea. During the first 1-2 weeks following the initial injection, estradiol levels increase and then decline to menopausal levels. The transient increase in estradiol levels may be associated with temporary worsening of signs and symptoms of endometriosis (see WARNINGS AND PRECAUTIONS section).

Triptorelin 3.75 mg was found to be generally safe and well tolerated in women with endometriosis treated for up to 6 months with the drug. Most adverse reactions did not result in discontinuation and most resolved spontaneously without further medical intervention. The most frequently reported adverse reactions were those related to hypoestrogenism.

A small number of women have been inadvertently exposed to triptorelin during pregnancy. Of 28 pregnant women in France exposed to triptorelin in fertility trials, one case of trisomy 13 was reported in a women who received triptorelin 15 days after conception. One case of trisomy 18 has been reported in Italy. In both cases, a causal relationship could not be established. In another study, very long fetal exposure to triptorelin in a woman who became pregnant during a clinically- induced pseudomenopause resulted in the term delivery of a healthy newborn.

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.

In a controlled study comparing triptorelin [3.75 mg] and leuprolide [3.75 mg] administered monthly for 6 months to endometriosis patients, the following adverse events were reported by 1% or more of patients in the triptorelin study group regardless of relationship or association to treatment:

TABLE 1: ADVERSE EVENTS REPORTED BY 1% OR MORE OF PATIENTS DURING TREATMENT WITH TRIPTORELIN
Adverse Event Triptorelin
(n = 67)
% of patients
Body As A Whole
Ankle edema (edema dependent)
Pain, nos*
Back pain
Accidental injury
Bruising
Fatigue

23.9
11.9
9.0
7.5
6.0
3.0
Central and Peripheral Nervous System Disorders
Headache
Dizziness

59.7
6.0
Endocrine Disorders
Breast disorder

31.3
Gastrointestinal Disorders
Nausea
Abdominal pain
Vomiting

13.4
10.4
3.0
Musculoskeletal Disorders
Arthralgia

7.5
Psychiatric
Insomnia
Depression
Decreased libido
Irritability

68.7
56.7
53.7
44.8
Reproductive Disorders
Vaginal dryness
Pelvic pain

49.3
3.0
Resistance Mechanism Disorders
Viral infection

13.4
Skin and Appendages Disorders
Increased sweating
Seborrhea
Acne

85.1
43.3
29.9
Urinary System
Urinary tract infection

6.0
Vascular (extracardiac) Disorders
Hot flushes

91.0

Dose of drug administered was 3.75 mg IM every four weeks for six months (6 injections).
*nos = not otherwise specified

Frequently reported adverse events for both the triptorelin and leuprolide groups included hot flushes, depression, irritability, headache, breast disorder, arthralgia, insomnia, decreased libido, acne, seborrhea, increased sweating, and vaginal dryness.

Infrequent (< 5% of women) adverse events included, but were not limited to, injection site reaction, chest pain, rash, peripheral edema, leg cramps, diarrhea, irritable bowel, arthritis, arthrosis, myalgia, amnesia, apathy, leukorrhea, and vaginal hemorrhage.

Changes in Bone Mineral Density: After 6 months of treatment with triptorelin in 32 women, the average decrease in bone mineral density, as measured by dual energy x-ray absorptiometry, was 5.3% and 2.3% in lumbar spine and hip, respectively, compared to pretreatment values. Lumbar spine and hip bone mineral density were still slightly decreased by 12 months follow-up (1.7% and 1.3%, respectively).

Abnormal Hematologic and Clinical Chemistry Findings

For the most part, hematology test results were within normal limits throughout the study for patients in each treatment group with available data. Minor fluctuations in values were observed at various time points in each of the treatment groups, none of which were considered clinically meaningful. With the exception of serum and urine creatinines, which were relatively low throughout the study, chemistry results were generally within normal limits for most patients throughout the study.

Post-Market Adverse Drug Reactions

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 section).

Drug interactions

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 would not be prescribed concomitantly with triptorelin 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 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.

In clinical trials, there were no clinically meaningful changes in laboratory values during or following triptorelin therapy. Triptorelin therapy had no significant effect on liver enzymes (ALT/AST), alkaline phosphatase, LDH, total bilirubin, urea or inorganic phosphorous during the study. Likewise, there was no significant treatment effect on hematology parameters (WBC, RBC, hemoglobin, hematocrit, platelet count, or WBC differential).

Dosage and administration

Recommended Dose and Dosage Adjustment

The recommended dose of TRELSTAR (triptorelin for injectable suspension) for the management and relief of chronic pain associated with endometriosis is a monthly intramuscular injection of 3.75 mg (as peptide base) incorporated in a depot formulation every 28 days for no longer than 6 months.

Administration

TRELSTAR is administered monthly as a single intramuscular injection.

Missed Dose

Maintaining estradiol suppression is important in the management and relief of chronic pain associated with endometriosis. Missing an appointment by a few days should not disrupt the benefits of treatment, but keeping a consistent schedule of TRELSTAR injections is an important part of treatment.

Reconstitution

TRELSTAR is supplied in a single-dose vial 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 dose delivery system (with Sterile Water for Injection), MIXJECT; and the TRELSTAR 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. This is equivalent to 3.75 mg of triptorelin peptide base units intended as a single monthly 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 vial (with Sterile Water for Injection), MIXJECT:

Please read the instructions completely before you begin.


MIXJECT Preparation

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


Instructions for Use – TRELSTAR vial (without Sterile Water for Injection)

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.

Preparation

  1. 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.
  2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.
  3. Withdraw the entire content of the reconstituted suspension into the syringe and inject it immediately.

Disposal

Dispose of the syringe and vial into a suitable sharps container.

Overdosage

The pharmacologic properties of TRELSTAR (triptorelin for injectable suspension) 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

TRELSTAR (triptorelin for injectable suspension) 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 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 estradiol. However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of ovarian steroidogenesis. In premenopausal women, circulating estrogen is decreased to postmenopausal levels (Table 2). This results in accessory sexual organ atrophy which is generally reversible upon discontinuation of drug therapy.

TABLE 2. ESTRADIOL LEVEL (PMOL/L) PROFILE OVER 24 WEEKS OF TREATMENT WITH TRIPTORELIN (N=66)
Week 0
Pretreatment
Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
Mean 124 48 48 52 51 52 46
SD 77 42 36 37 35 36 25

A single intramuscular (IM) dose of 1.9, 3.75, or 7.5 mg to women with endometriosis, uterine myoma or dysfunctional bleeding resulted in transient dose-dependent increase in LH and estradiol following injection. By day 14, serum LH and estradiol concentrations decreased to levels typically seen in postmenopausal women. On day 28 and up to day 42 after injection, estradiol levels were still suppressed (<184 pmol/L) in the mid- and high-dose groups. Following LHRH challenge (100 mg) on day 28, 7/10 patients in the 1.9 mg group, 3/10 patients in the 3.75 mg group, and 0/10 patients in the 7.5 mg group responded to stimulation with increased LH levels. By day 56, estradiol concentrations returned to pretreatment levels in the mid-dose group but were still suppressed in the high dose group (7/8 patients).

Pharmacokinetics

Results of pharmacokinetic investigations conducted in both women and men indicate that after IV bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model with elimination from the central compartment and corresponding distribution half-lives of approximately 3 minutes, 47 minutes, and 5 hours in women and 6 minutes, 45 minutes, and 3 hours in men.

Absorption

Triptorelin is not active when given orally. Following a single intramuscular injection of the sustained release formulation in healthy male volunteers, mean peak triptorelin serum concentration was 28.4 ng/mL at 1-3 hours and 0.084 ng/mL at 4 weeks (Table 3). In this study, absolute bioavailability of intramuscular triptorelin relative to intravenous triptorelin (F based on AUC) was approximately 83%.

TABLE 3. PHARMACOKINETIC PARAMETERS OF TRIPTORELIN FOLLOWING AN INTRAMUSCULAR ADMINISTRATION OF TRELSTAR IN HEALTHY MALE VOLUNTEERS (mean ± SD or median (range) for Tmax)
Triptorelin Pharmacokinetics
No. of Subjects Cmax
(ng/mL)
Tmax
(h)
AUC
(h·ng/mL)
F (%)*
(No. of days)
20 28.43 ± 7.31 1.0 (1.0 - 3.0) 223.15 ± 46.96 83 (28 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 μg IV bolus of triptorelin).

Distribution

The volume of distribution of triptorelin following IV administration of 0.5 mg triptorelin was approximately 30-33 L in healthy male volunteers and women with endometriosis.

Metabolism

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 section).

Following a 0.5 mg IV bolus dose to 19 women, the total clearance was estimated to be 110 mL/min. Twenty percent of the dose was eliminated in the urine (Table 4).

TABLE 4. PHARMACOKINETIC PARAMETERS FOLLOWING IV ADMINISTRATION OF TRIPTORELIN TO WOMEN WITH ENDOMETRIOSIS OR UTERINE MYOMA
Dose
(No. of subjects)
Cmax(ng/mL)1 Tmax
(h)2           
AUC (h·ng/mL)1 t1/23
(h)1     
Clp (mL/min)1 Vss
(L)1     
% elimin. Urine1
0.5 mg IVB
(n=19)
115.8±59.0 0.03
(0.03-0.17)
81.9 ± 32.9 5.37 ±2.29 110 ± 40 32.9 ±16.8 20 ± 10

1 Mean ± SD
2 Median (range)
3 Elimination half-life

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 5). 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 5. PHARMACOKINETIC PARAMETERS (MEAN ±SD) IN HEALTHY VOLUNTEERS AND SPECIAL POPULATIONS
Group Cmax
(ng/mL)
AUCinf
(h·ng/mL)
Clp 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
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 section) 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.

Storage and stability

Store TRELSTAR vial supplied with MIXJECT Dose Delivery System (with Sterile Water for Injection) at 20-25oC; excursions permitted: 15-30oC.

Store TRELSTAR vial (without Sterile Water for Injection) at 20-25oC; excursions permitted: 15 - 30oC.

Do Not Freeze. Protect from light.

Unused portion of reconstituted TRELSTAR should be discarded immediately.

Keep out of reach of children.

Dosage forms, composition and packaging

TRELSTAR (1 month slow-release) 3.75 mg triptorelin/vial

TRELSTAR 3.75 mg 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, mannitol, carboxymethylcellulose sodium, and polysorbate 80. 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 is available in two presentations:

TRELSTAR dose delivery system (with Sterile Water for Injection), MIXJECT: The accompanying pre-filled syringe contains 2 mL Sterile Water for Injection.

TRELSTAR vial (without Sterile Water for Injection)