6800112052544E1
Revised: August 2006
(Place for bar code)
Watson Pharma, Inc.
TRELSTAR^® LA 11.25 mg
(triptorelin pamoate for injectable suspension)

TRELSTAR LA contains a pamoate salt of triptorelin, and triptorelin is a synthetic decapeptide agonist analog of luteinizing hormone releasing hormone (LHRH or GnRH) with greater potency than the naturally occurring LHRH. The chemical name of triptorelin pamoate is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycine amide (pamoate salt); the empirical formula is C₆₄H₈₂N₁₈O₁₃ · C₂₃H₁₆O₆ and the molecular weight is 1699.9. The structural formula is shown below.

TRELSTAR LA is a sterile, lyophilized biodegradable microgranule formulation supplied as a single-dose vial containing triptorelin pamoate (11.25 mg as the peptide base), 145 mg poly-d,l-lactide-co-glycolide, 85 mg mannitol, USP,  30 mg carboxymethylcellulose sodium, USP, 2 mg polysorbate 80, NF. When 2 mL sterile water for injection is added to the vial containing TRELSTAR LA and mixed, a suspension is formed which is intended as an intramuscular injection to be administered every 84 days (ie, every 12 weeks). TRELSTAR LA is available in 2 packaging configurations: (a) TRELSTAR LA vial alone or (b) TRELSTAR LA vial plus a separate pre-filled syringe that contains sterile water for injection, USP, 2 mL, pH 6 to 8.5 (Clip'n'Ject^®).

Triptorelin is a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. 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). 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 and ovarian steroidogenesis is observed. In men, 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 (IM) injection of TRELSTAR LA to men with advanced prostate cancer, serum testosterone levels first increased, peaking on days 2-3, and declined thereafter to low levels by weeks 3-4.

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous (IV) 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.

TRELSTAR LA is indicated in the palliative treatment of advanced prostate cancer. It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient.

TRELSTAR LA is contraindicated in individuals with a known hypersensitivity to triptorelin or any other component of the product, other LHRH agonists or LHRH.

TRELSTAR LA is contraindicated in women who are or may become pregnant while receiving the drug. TRELSTAR LA may cause fetal harm when administered to a pregnant woman.

Rare reports of anaphylactic shock and angioedema related to triptorelin administration have been reported. In the event of a reaction, therapy with TRELSTAR LA should be discontinued immediately and the appropriate supportive and symptomatic care should be administered.

Initially, triptorelin, like other LHRH agonists causes a transient increase in serum testosterone levels. As a result, isolated cases of worsening of signs and symptoms of prostate cancer during the first weeks of treatment have been reported with LHRH agonists. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral 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 develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered.

Patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS). Hypersensitivity and anaphylactic reactions have been reported with triptorelin with other LHRH agonists (see CONTRAINDICATIONS and WARNINGS).

Response to TRELSTAR LA should be monitored by measuring serum levels of testosterone and prostate-specific antigen. Testosterone levels should be measured immediately prior to or immediately after dosing.

No drug-drug interaction studies involving triptorelin have been conducted. In the absence of relevant data as a precaution, hyperprolactinemic drugs should not be prescribed concomitantly with TRELSTAR LA since hyperprolactinemia reduces the number of pituitary GnRH receptors.

Chronic or continuous administration of triptorelin in therapeutic doses results in suppression of pituitary-gonadal axis. Diagnostic tests of the pituitary-gonadal function conducted during treatment and after cessation of therapy may therefore be misleading.

In rats, doses of 120, 600, and 3000 mcg/kg given every 28 days (approximately 0.3, 2, and 8 times the recommended human therapeutic dose based on body surface area) resulted in increased mortality with a drug treatment period of 13-19 months. The incidence 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 therapeutic 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 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, 2.0, and 16 times the recommended human therapeutic dose based on body surface area) or 20 mcg/kg/day in slow release microspheres, had no effect on the fertility or general reproductive performance of female rats. Treatment did not elicit embryotoxicity, teratogenicity, or any effects on the development of the offspring (F₁ generation) or their reproductive performance.

No studies were conducted to assess the effect of triptorelin on male fertility.

Prostate cancer occurs primarily in an older patient population. Clinical studies with TRELSTAR LA have been conducted primarily in patients ≥ 65 years old.

TRELSTAR LA has not been studied in women and is not indicated for use in women.

It is not known whether TRELSTAR LA is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of TRELSTAR LA on lactation and/or the breastfed child have not been determined, TRELSTAR LA should not be used by nursing mothers.

TRELSTAR LA has not been studied in pediatric patients and is not indicated for use in pediatric patients.

In the majority of patients, testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment. The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, hematuria, and bladder outlet obstruction. Isolated cases of spinal cord compression with weakness or paralysis of the lower extremities have occurred (see WARNINGS).

In a controlled, comparative clinical trial, the following adverse reactions were reported to have a possible or probable relationship to therapy as ascribed by the treating physician in 1% or more of the patients receiving triptorelin (Table 3). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related or unlikely to be related are excluded.

Changes in Laboratory Values During Treatment: The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients at the Day 253 visit: decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase. The relationship of these changes to drug treatment is difficult to assess in this population.

Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

There is no experience of overdosage in clinical trials. In single dose toxicity studies in mice and rats, the subcutaneous LD₅₀ of triptorelin was 400 mg/kg in mice and 250 mg/kg in rats, approximately 7000 and 4000 times, respectively, the usual human dose. If overdosage occurs however, therapy should be discontinued immediately and the appropriate supportive and symptomatic treatment administered.

TRELSTAR LA Must Be Administered Under the Supervision of a Physician.

The recommended dose of TRELSTAR LA is 11.25 mg incorporated in a long acting formulation administered every 84 days as a single intramuscular injection administered in either buttock. The lyophilized microgranules are to be reconstituted in sterile water. No other diluent should be used. Reconstitute in accord with the following:

For TRELSTAR LA:

• Using a syringe fitted with a sterile 20-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.

• Slowly withdraw the entire spans of the reconstituted suspension into the syringe.

• Inject the patient in either buttock with the spans of the syringe.

For the TRELSTAR LA Clip'n'Ject^® single-dose delivery system, see adjacent INSTRUCTIONS FOR CLIP'N'JECT® USE section.

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

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

TRELSTAR LA (NDC 52544-154-02) is supplied in a single-dose vial with a flip-off seal containing sterile lyophilized triptorelin pamoate microgranules equivalent to 11.25 mg triptorelin peptide base, incorporated in a biodegradable copolymer of lactic and glycolic acids. A single dose vial of TRELSTAR LA contains triptorelin pamoate (11.25 mg as peptide base units), poly-d,l-lactide-co-glycolide (145 mg), mannitol, USP (85 mg), carboxymethylcellulose sodium, USP (30 mg), and polysorbate 80, NF (2 mg).

TRELSTAR LA (NDC 52544-154-76) is also supplied in the TRELSTAR LA Clip'n'Ject^® single-dose delivery system consisting of a vial with a flip-off seal containing sterile lyophilized triptorelin pamoate microgranules equivalent to 11.25 mg of triptorelin peptide base, incorporated in a biodegradable copolymer of lactic and glycolic acids, and a pre-filled syringe containing sterile water for injection, USP, 2 mL, pH 6 to 8.5.

When mixed with sterile water for injection, TRELSTAR LA is administered every 84 days as a single intramuscular injection.

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Do not freeze.

Rx only

Product No. 1120-02
Revised: August 2006

S0806

U.S. Patent Nos.: 5,134,122; 5,225,205; 5,192,741.

Clip'n'Ject and Flip-Off button are manufactured by and are registered trademarks of West Pharmaceutical Services, Inc.  Lionville, PA 19341 USA

Tyvek^® is a registered trademark of E.I. du Pont de Nemours and Company

Manufactured for:
Watson Pharma, Inc.
A subsidiary of Watson Pharmaceuticals, Inc.
Corona, CA 92880  USA
by: Debio RP
CH-1920 Martigny, Switzerland

Before you begin read complete instructions.

Clip'n'Ject^® Preparation

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^® vial on a clean, flat surface that is covered with a sterile pad or cloth. Peel the Tyvek^® cover away from the buler package, and place the vial, connector, alcohol swab, and plunger rod on the prepared surface. Be sure to begin by removing the Flip-Off^® 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.

Clip'n'Ject^® Activation

Clip'n'Ject^® Disposal

After administering Trelstar^®, 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.