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Safe use of nafarelin acetate in pregnancy has not been established clinically. Before starting treatment with SYNAREL, pregnancy must be excluded.

When used regularly at the recommended dose, SYNAREL usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking SYNAREL, particularly if patients miss successive doses. Therefore, patients should use nonhormonal methods of contraception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus.

General

As with other drugs that stimulate the release of gonadotropins or that induce ovulation, ovarian cysts have been reported to occur in the first two months of therapy with SYNAREL. Many, but not all, of these events occurred in patients with polycystic ovarian disease. These cystic enlargements may resolve spontaneously, generally by about four to six weeks of therapy, but in some cases may require discontinuation of drug and/or surgical intervention.

Information for Patients

An information pamphlet for patients is included with the product. Patients should be aware of the following information:

1. Because menstruation should stop with effective doses of SYNAREL, the patient should notify her physician if regular menstruation persists. The cause of vaginal spotting, bleeding or menstruation could be noncompliance with the treatment regimen, or it could be that a higher dose of the drug is required to achieve amenorrhea. The patient should be questioned regarding her compliance. If she is careful and compliant, and menstruation persists to the second month, consideration should be given to doubling the dose of SYNAREL. If the patient has missed several doses, she should be counseled on the importance of taking SYNAREL regularly as prescribed.
2. Patients should not use SYNAREL if they are pregnant, breastfeeding, have undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in SYNAREL.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a nonhormonal method of contraception should be used during treatment. Patients should be advised that if they miss successive doses of SYNAREL, breakthrough bleeding or ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.
4. Those adverse events occurring most frequently in clinical studies with SYNAREL are associated with hypoestrogenism; the most frequently reported are hot flashes, headaches, emotional lability, decreased libido, vaginal dryness, acne, myalgia, and reduction in breast size. Estrogen levels returned to normal after treatment was discontinued. Nasal irritation occurred in about 10% of all patients who used intranasal nafarelin.
5. The induced hypoestrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible. During one six-month treatment period, this bone loss should not be important. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, therapy with SYNAREL may pose an additional risk. In these patients the risks and benefits must be weighed carefully before therapy with SYNAREL is instituted. Repeated courses of treatment with gonadotropin releasing hormone analogs are not advisable in patients with major risk factors for loss of bone mineral content.
6. Patients with intercurrent rhinitis should consult their physician for the use of a topical nasal decongestant. If the use of a topical nasal decongestant is required during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL.
   Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, because this may impair drug absorption.
7. Retreatment cannot be recommended because safety data beyond 6 months are not available.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560 times the maximum recommended human intranasal dose, respectively). These multiples of the human dose are based on the relative bioavailability of the drug by the two routes of administration. As seen with other GnRH agonists, nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors in the treated groups. There was a dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was a dose-related increase in Harderian gland tumors in males and an increase in pituitary adenomas in high-dose females. No metastases of these tumors were observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal stimulation.

Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and mammalian systems. These studies provided no evidence of mutagenic potential.

Reproduction studies in male and female rats have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated.

Pregnancy, Teratogenic Effects

Pregnancy Category X. See 'CONTRAINDICATIONS.' Intramuscular SYNAREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day (about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on the relative bioavailability by the two routes of administration). An increase in major fetal abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and 0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was a dose-related increase in fetal mortality and a decrease in fetal weight with the highest dose.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness of SYNAREL for endometriosis in patients younger than 18 years have not been established.

Last reviewed on RxList: 1/30/2012
This monograph has been modified to include the generic and brand name in many instances.