8****USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Data

Animal Data

Studies in pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area) during the period of organogenesis demonstrated maternal toxicity and embryo-fetal toxicities. Embryo-fetal toxicities consisted of pre-implantation loss, increased resorption, and reduced mean number of viable fetuses at the high dose. Teratogenic effects were not observed in viable fetuses in rats or mice. Doses administered to mice were 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, and 7 times the estimated human daily dose based on body surface area).

8.2 Lactation

The safety and efficacy of TRELSTAR have not been established in females. There are no data on the presence of triptorelin in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child. Because of the potential for serious adverse reactions in a breastfed child from TRELSTAR, a decision should be made to either discontinue breastfeeding, or discontinue the drug taking into account the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential

Infertility

Males

Based on mechanism of action, TRELSTAR may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Prostate cancer occurs primarily in an older population. Clinical studies with TRELSTAR have been conducted primarily in patients ≥ 65 years [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.6 Renal Impairment

Subjects with renal impairment had higher exposure than young healthy males [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Subjects with hepatic impairment had higher exposure than young healthy males [see Clinical Pharmacology (12.3)].

11****DESCRIPTION

TRELSTAR is a white to slightly yellow lyophilized cake. When reconstituted, TRELSTAR has a milky appearance. It contains a pamoate salt of triptorelin, a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). 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:

Structural formula for TRELSTAR (triptorelin pamoate).

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

Table 5. TRELSTAR Composition

Ingredients	TRELSTAR**** 3.75 mg	TRELSTAR**** 11.25 mg	TRELSTAR**** 22.5 mg
triptorelin pamoate (base units)	3.75 mg	11.25 mg	22.5 mg
poly-d,l-lactide-co-glycolide	138 mg	120 mg	183 mg
mannitol, USP	71 mg	74 mg	74 mg
carboxymethylcellulose sodium, USP	25 mg	26 mg	26 mg
polysorbate 80, NF	1.7 mg	1.7 mg	1.7 mg

When 2 mL sterile water is added to the vial containing TRELSTAR and mixed, a suspension is formed which is intended as an intramuscular injection. TRELSTAR is available in a vial plus a MIXJECT vial adapter, and a separate pre-filled syringe that contains sterile water for injection, USP, 2 mL.

13****NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In rats, triptorelin 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.