Trelstar: Indications, Dosage, Precautions, Adverse Effects
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Trelstar - 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
IntramuscularPowder (microgranules) for slow-release suspension
3.75 mg of triptorelin peptide base units/vial; 11.25 mg of triptorelin peptide base units/vial; 22.5 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 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 were 65 years and older (see CLINICAL TRIALS section).

Pediatrics (<18 years of age)

The safety and effectiveness of TRELSTAR in pediatric patients have not been established (see WARNINGS AND PRECAUTIONS section).

TRELSTAR must be administered under the supervision of a physician.

Contraindications

  • TRELSTAR 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 section). For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • TRELSTAR are 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).

Warnings and precautions

Serious Warnings and Precautions

TRELSTAR (triptorelin for injectable suspension) should be prescribed by a qualified physician experienced in the use of hormonal therapy in prostate cancer. TRELSTAR should be administered by a health professional.

The following are clinically significant adverse events:
  • Clinical testosterone flare reaction in men with prostate cancer (see General below)
  • Osteoporosis (see Endocrine and Metabolism below)

General

TRELSTAR (triptorelin for injectable suspension), like other LHRH agonists, causes 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 LHRH 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 TRELSTAR therapy under close supervision.

Hypersensitivity and anaphylactic reactions have been reported with TRELSTAR as with other LHRH agonists (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions section).

During post-marketing experience, 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.

Carcinogenesis and Mutagenesis

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

Cardiovascular

There may be a relationship between androgen deprivation therapy and cardiovascular risk in men with prostate cancer on the basis of the demonstrated adverse impact of androgen deprivation on traditional cardiovascular risk factors, including serum lipoproteins, insulin sensitivity, and obesity (see the References section). Reports of events related to cardiovascular ischemia including myocardial infarction, stroke and cardiovascular-related deaths have been received in patients treated with LHRH agonists. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential cardiovascular risk. Assessment of cardiovascular risk and management according to local clinical practice and guidelines should be considered (see Monitoring and Laboratory Tests below).

Effect on QT/QTc interval

The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with TRELSTAR therapy.

Androgen deprivation therapy has the potential to prolong QT/QTc interval on ECG. QT prolongation is a physiologic consequence of hormonal therapies that induce androgen ablation in males with prostate cancer and should be considered in assessing the risk-benefit of treatment with hormonal therapy. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risk in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA (e.g. quinidine, procainamide), Class III (e.g. aminodarone, sotalol, dofetilide, ibutilide), or Class IC (e.g. flecainide, propafenone) antiarrhythmic medications.

Endocrine and Metabolism

Changes in bone density

Decreased bone mineral density can be anticipated with long term use of an LHRH agonist. Androgen deprivation therapy is associated with increased risks of osteoporosis and skeletal bone fractures. The risk of skeletal fracture increases with the duration of androgen deprivation therapy. Assessment of osteoporosis risk and management according to clinical practice and guidelines should be considered.

In patients with significant risk factors for decreased bone mineral content and/or bone mass such as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis, chronic use of drug that can reduce bone mass such as anticonvulsants or corticosteroids, TRELSTAR may pose additional risk. In these patients, risk versus benefit must be weighed carefully before therapy with TRELSTAR is instituted.

Hypogonadism

Long-term administration of TRELSTAR 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.

Reduction in glucose tolerance

A reduction in glucose tolerance and an increased risk in developing diabetes have been reported in men treated with androgen deprivation therapy. Patients treated with TRELSTAR should undergo periodic monitoring of blood glucose.

Diabetic patients may require more frequent monitoring when receiving TRELSTAR.

Hematologic

Anemia is a known physiologic consequence of testosterone suppression. Assessment of anemia risk and management according to local clinical practice and guidelines should be considered.

Neurologic

No studies on the effects of TRELSTAR on the ability to drive and use machines have been performed. However, fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.

Psychiatric

There is an increased risk of depression (which may be severe) in patients undergoing treatment with GnRH agonists, including TRELSTAR. Patients should be informed accordingly and treated appropriately if symptoms occur.

Patients with known depression should be monitored closely during therapy.

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

Pregnant Women

The safe use of TRELSTAR during pregnancy has not been established clinically. 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 (see CONTRAINDICATIONS section).

Nursing Women

It is not known to what extent triptorelin is excreted into human milk and caution should be exercised when TRELSTAR is administered to nursing women. (see CONTRAINDICATIONS section).

Geriatrics (> 65 years of age)

The majority of the patients studied in the clinical trials for TRELSTAR were 65 years and older.

Pediatrics (< 18 years of age)

The safety and effectiveness of TRELSTAR in pediatric patients have not been established.

Race

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 (3-month, 11.25 mg triptorelin pamoate formulation), included 47.7% Caucasian, 37.6% Black, and 14.7% Other patients. In the non-comparative clinical study conducted to determine the safety and efficacy of TRELSTAR (6-month, 22.5 mg triptorelin pamoate formulation), 64.2% of the patients were Caucasian, 22.5% were Black, and 13.3% were Other.

Monitoring and Laboratory Tests

During therapy with TRELSTAR, patients should be routinely monitored by physical examinations and appropriate laboratory tests.

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.

Response to TRELSTAR may be monitored by periodically measuring serum concentrations of testosterone and prostate specific antigen (PSA). Results of testosterone determinations are dependent on assay methodology. Some methods may either over- or underestimate the testosterone values in the hypogonadal testosterone range. The LC-MS/MS method is the reference method for testosterone assessments when castrate levels are expected and was the assay method used in the clinical study supporting authorization of TRELSTAR 22.5 mg (6- month slow-release). It is advisable to be aware of the type and precision of the assay methodology in order to make appropriate clinical and therapeutic decisions.

Baseline risk factors of cardiovascular diseases should be assessed. Patients receiving TRELSTAR should be monitored periodically for risk factors, signs and symptoms of cardiovascular diseases. In addition, baseline ECG recording and serum potassium, calcium, and magnesium levels are recommended. Monitoring of ECG and serum electrolyte levels during treatment should also be considered for those at risk for electrolyte abnormality and QT prolongation (see WARNINGS AND PRECAUTIONS, Cardiovascular section).

Blood glucose levels and/or glycosylated haemoglobin (HbA1c) should be checked periodically in patients treated with TRELSTAR and more frequently in diabetic patients (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism section).

Adverse reactions

Adverse Drug Reaction Overview

TRELSTAR 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 TRELSTAR treatment. Postmarketing reports of anaphylactic shock and angioedema have been reported following TRELSTAR administration (see WARNINGS AND PRECAUTIONS section). 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 TRELSTAR treatment were due to the expected physiological effects related to decreased testosterone levels. These effects included hot flushes, impotence, and decreased libido. TRELSTAR, like other LHRH 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 section).

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 µg triptorelin s.c. for the first month. In the second study, all patients received 100 µg 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 section).

Clinical Studies with Triptorelin Pamoate

TRELSTAR 3.75 mg (1-month, 3.75 mg triptorelin pamoate formulation) and TRELSTAR 11.25 mg (3-month, 11.25 mg triptorelin pamoate formulation)

The safety of TRELSTAR was also evaluated in a study that compared TRELSTAR (1-month, 3.75 mg triptorelin pamoate formulation) and TRELSTAR (3-month, 11.25 mg triptorelin pamoate formulation). The patients in this study were randomized to receive either three injections of TRELSTAR 3-month formulation (11.25 mg), administered i.m. every 84 days for 9 months, or nine injections of TRELSTAR 1-month formulation (3.75 mg), administered i.m. every 28 days for 9 months.

The safety results showed that the two formulations of TRELSTAR were well tolerated.

TRELSTAR 22.5 mg (6-month, 22.5 mg triptorelin pamoate formulation)

The safety of TRELSTAR was evaluated in a non-comparative study of TRELSTAR (6-month, 22.5 mg triptorelin pamoate formulation). Each patient in this study received two injections of TRELSTAR 6-month formulation (22.5 mg), with the first injection administered i.m. on Day 1 and the second injection administered i.m. on Day 169.

The safety results showed that the 6-month formulation (TRELSTAR 22.5 mg) was well tolerated.
The safety profile was similar to the 1-month (TRELSTAR 3.75 mg) and 3-month (TRELSTAR 11.25 mg) formulations.

The following possibly or probably related systemic adverse events were reported by 1% or more of patients in the studies mentioned above for TRELSTAR 3.75, TRELSTAR 11.25 and TRELSTAR 22.5 mg:

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), TRELSTAR 11.25 MG (1 INJECTION EVERY 84 DAYS FOR 9 MONTHS), AND TRELSTAR 22.5 MG (1 INJECTION ON DAY 1 AND 1 INJECTION ON DAY 169)
Adverse EventsTRELSTAR
(3.75 mg)1
N = 172
n (%)
TRELSTAR
(11.25 mg)1
N=174
n (%)
TRELSTAR
(22.5 mg)2
N = 120
n (%)
Application Site Disorders
Injection site bruising
Injection site induration
Injection site pain

0 (0.0)
0 (0.0)
2 (1.2)

0 (0.0)
0 (0.0)
7 (4.0)

2 (1.7)
2 (1.7)
2 (1.7)
Body as a Whole
Hot flushes*
Back pain
Pain
Leg pain
Fatigue
Chest pain
Lethargy
Asthenia
Oedema peripheral
Allergic reaction

114 (66.3)
6 (3.5)
10 (5.8)
5 (2.9)
5 (2.9)
0 (0.0)
0 (0.0)
2 (1.2)
3 (1.7)
2 (1.2)

127 (73.0)
5 (2.9)
6 (3.4)
9 (5.2)
4 (2.3)
3 (1.7)
0 (0.0)
2 (1.1)
2 (1.1)
0 (0.0)

86 (71.7)
0 (0.0)
0 (0.0)
0 (0.0)
5 (4.2)
0 (0.0)
2 (1.7)
0 (0.0)
0 (0.0)
0 (0.0)
Cardiovascular Disorders
Hypertension
Oedema dependant

8 (4.7)
0 (0.0)

7 (4.0)
4 (2.3)

0 (0.0)
0 (0.0)
Central and Peripheral
Nervous System Disorders

Headache
Dizziness
Cramps legs


7 (4.1)
5 (2.9)
1 (0.6)


12 (6.9)
5 (2.9)
3 (1.7)


2 (1.7)
2 (1.7)
0 (0.0)
Endocrine Disorders
Breast pain male
Gynecomastia

5 (2.9)
0 (0.0)

4 (2.3)
3 (1.7)

0 (0.0)
0 (0.0)
Gastro-intestinal System Disorders
Constipation
Nausea
Diarrhoea
Abdominal pain
Dyspepsia

4 (2.3)
7 (4.1)
4 (2.3)
1 (0.6)
2 (1.2)

3 (1.7)
5 (2.9)
2 (1.1)
2 (1.1)
3 (1.7)

0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Heart Rate and Rhythm Disorders
Palpitation

3 (1.7)

0 (0.0)

0 (0.0)
Liver and Biliary System Disorders
Hepatic function abnormal

0 (0.0)

2 (1.1)

0 (0.0)
Metabolic and Nutritional
Disorders

Oedema legs
Diabetes mellitus


14 (8.1)
2 (1.2)


11 (6.3)
1 (0.6)


0 (0.0)
0 (0.0)
Musculo-skeletal
Disorders

Skeletal pain
Arthralgia
Myalgia


20 (11.6)
4 (2.3)
1 (0.6)


23 (13.2)
4 (2.3)
2 (1.1)


0 (0.0)
0 (0.0)
0 (0.0)
Psychiatric Disorders
Insomnia
Depression*
Impotence*
Anorexia
Libido decreased*

2 (1.2)
3 (1.7)
7 (4.1)
1 (0.6)
1 (0.6)

3 (1.7)
1 (0.6)
4 (2.3)
3 (1.7)
4 (2.3)

0 (0.0)
2 (1.7)
12 (10.0)
0 (0.0)
2 (1.7)
Reproductive System and
Breast Disorders

Testicular atrophy*


0 (0.0)


0 (0.0)


9 (7.5)
Respiratory System Disorders
Coughing
Dyspnoea
Pharyngitis

1 (0.6)
3 (1.7)
0 (0.0)

3 (1.7)
2 (1.1)
2 (1.1)

0 (0.0)
0 (0.0)
0 (0.0)
Skin and Appendages
Disorders

Rash
Pruritus

1 (0.6)
2 (1.2)

3 (1.7)
0 (0.0)

0 (0.0)
0 (0.0)
Urinary System Disorders
Urinary tract infection
Dysuria
Urinary retention

3 (1.7)
3 (1.7)
0 (0.0)

0 (0.0)
8 (4.6)
2 (1.1)

0 (0.0)
0 (0.0)
0 (0.0)
Vision Disorders
Eye pain
Conjunctivitis

1 (0.6)
0 (0.0)

2 (1.1)
2 (1.1)

0 (0.0)
0 (0.0)

* Expected pharmacological consequence of testosterone suppression
1 Adverse reactions for TRELSTAR 3.75 mg and TRELSTAR 11.25 mg are coded using the WHO Adverse Reactions Terminology (WHOART)
2 Adverse reactions for TRELSTAR 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA)

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 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. Adverse drug reactions that were reported by 1% or less of subjects (N = 1; 0.83%) in the TRELSTAR 22.5 mg study, and were considered to be possibly or probably related to study drug, included the following: abdominal discomfort, abdominal pain, constipation, nausea, injection site erythema, injection site pruritus, injection site swelling, alanine aminotransferase increased, aspartate aminotransferase increased, prostatic antigen increased, weight increased, anorexia, arthralgia, back pain, musculoskeletal stiffness, myalgia, pain in extremity, metastatic pain, paraesthesia, syncope vasovagal, insomnia, loss of libido, orchitis noninfective, pruritus, rash, and hypertension.

Abnormal Hematologic and Clinical Chemistry Findings

The incidence rates 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 3.75 mg and TRELSTAR 11.25 mg. The following abnormalities in laboratory values not present at baseline, which were similar with the 3.75 mg and 11.25 mg formulation, were observed in 10% or more of patients for TRELSTAR 22.5 mg: decreased hemoglobin and RBC count and increased glucose (change from baseline to worst-case on-treatment). An increase in prothrombin time was observed in 4.9%, 10.5% and 13.6% of the patients for TRELSTAR 3.75 mg, 11.25 mg and 22.5 mg, respectively (change from baseline to worst-case on-treatment). The relationship of these changes to drug treatment is difficult to assess in this population.

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post approval use of TRELSTAR.

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.

Cases of anaphylactic shock and angioedema that were related to TRELSTAR have been reported during post-marketing surveillance.

During post-marketing experience, convulsions and thrombosis-related events including, but not limited to, pulmonary emboli, cerebrovascular accident, myocardial infarction, deep venous thrombosis, transient ischemic attack, and thrombophlebitis have been reported.

During post-marketing experience, worsening of pre-existing depression, including suicide attempts, has been reported in patients taking GnRH agonists, including TRELSTAR.

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 should not be prescribed concomitantly with TRELSTAR since hyperprolactinemia reduces the number of pituitary GnRH receptors.

Drug-Drug Interactions

Interactions with other drugs have not been established.

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of TRELSTAR with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes should be carefully evaluated. Such medicinal products include but are not limited to, the examples that follow: Class IA (e.g., quinidine, disopyramide), Class III (e.g., amiodarone, sotalol, dofetilide, ibutilide, dropedarone), or Class IC (e.g., flecainide, propafenone) antiarrhythmic medicinal products, antipsychotics (e.g., chlorpromazine), antibiotics and analogues (e.g., erythromycin, clarithromycin, azithromycin), quinolone antibiotics (e.g., moxifloxacin), antimalarials (e.g., quinine), azole antifungals, 5- hydroxytryptamine (5-HT3) receptor antagonists (e.g., ondansetron), and beta-2 adrenoceptor agonists (e.g., salbutamol).

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 TRELSTAR, 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.

Dosage and administration

Recommended Dose and Dosage Adjustment

TRELSTAR is intended for long-term administration unless clinically inappropriate.

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

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

The recommended dose of TRELSTAR 3.75 mg (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 the single dose delivery system, MIXJECT. Administer monthly as a single intramuscular injection, in accordance with the Instructions for use (see below).

TRELSTAR (3 month slow-release) 11.25 mg triptorelin/vial

The recommended dose of TRELSTAR 11.25 mg (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 the single dose delivery system, MIXJECT. Administer every 3 months as a single intramuscular injection, in accordance with the Instructions for use (see below).

TRELSTAR (6 month slow-release) 22.5 mg triptorelin/vial

The recommended dose of TRELSTAR 6 month slow-release (triptorelin for injectable suspension) is 22.5 mg (as peptide base), incorporated in a depot formulation, every 6 months. The lyophilized microgranules are to be reconstituted either with 2 mL of sterile water for injection utilizing a 21-gauge needle or using the single dose delivery system, MIXJECT. Administer every 6 months as a single intramuscular injection, in accordance with the Instructions for use (see below).

Administration

TRELSTAR is administered as a single intramuscular injection. Since TRELSTAR is a suspension of microgranules, inadvertent intravascular injection must be strictly avoided.

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

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 injections is an important part of treatment.

Reconstitution

TRELSTAR is 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 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. For TRELSTAR 3.75 mg (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 11.25 mg (3 month slow-release) this is equivalent to 11.25 mg of triptorelin peptide base units intended as a single 3 month intramuscular injection. For TRELSTAR 22.5 mg (6 month slow-release) this is equivalent to 22.5 mg of triptorelin peptide base units intended as a single 6 month intramuscular injection.

The suspension should be discarded if not used immediately after reconstitution.

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 Dose Delivery System (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 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

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 3.75 mg (triptorelin 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 11.25 mg (triptorelin for injectable suspension) as a 3 month sustained release formulation 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 11.25 mg every 3 months ensures that exposure to triptorelin is maintained with no clinically significant accumulation.

Following intramuscular injection of TRELSTAR (triptorelin for injectable suspension) as a 6 month sustained release formulation (22.5 mg) in patients with advanced prostate cancer, serum testosterone levels first increased, peaking on Day 3, and declined thereafter to low levels by Weeks 3 – 4. This suppression of testosterone, similar to castrate levels (<50 ng/dL), was maintained for 6 months after the first injection and on repeat administration. Intramuscular injection of TRELSTAR (22.5 mg) every 6 months ensures that exposure to triptorelin is maintained with no clinically significant accumulation.

Pharmacokinetics

Absorption

Triptorelin is not active when given orally. The pharmacokinetic parameters following single intramuscular injections of triptorelin 3.75 mg, 11.25 mg and 22.5 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 Tmax)
Triptorelin Pharmacokinetics
Dose
No. of Subjects
Cmax
(ng/mL)
Tmax
(h)
AUC
(h·ng/mL)
3.75 mg 20 healthy male volunteers28.43±7.311.0(1.0-3.0)223.15±46.96a
11.25 mg 13 prostate cancer patients38.5±10.52.0(2.0-4.0)2268.0±444.63b
22.5 mg 15 prostate cancer patients44.1±20.23.0(2.0–12.0)2674.88± 1040.03c

a AUC (0-28 d),b AUC (0-85 d),c AUC (0-169 d)

Distribution

The volume of distribution of triptorelin following IV administration of 0.5 mg triptorelin was approximately 30 L 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 section).

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 and Conditions section).

Special Populations and Conditions:

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
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
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 and Conditions, 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 3.75 mg, TRELSTAR 11.25 mg and TRELSTAR 22.5 mg supplied with MIXJECT Dose Delivery System (with Sterile Water for Injection) at 20-25oC: excursions permitted: 15 - 30oC.

Store TRELSTAR 3.75 mg, TRELSTAR 11.25 mg and TRELSTAR 22.5 mg vials (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, intramuscular injection administered monthly.

TRELSTAR (3 month slow-release) 11.25 mg triptorelin/vial

TRELSTAR 11.25 mg 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, 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, intramuscular injection administered every 3 months.

TRELSTAR (6 month slow-release) 22.5 mg triptorelin/vial

TRELSTAR 22.5 mg is supplied in a vial containing sterile lyophilized triptorelin pamoate microgranules which are equivalent to 22.5 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, intramuscular injection administered every 6 months.

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).