Synarel (Nafarelin)

SYNAREL®

Searle

Nafarelin

Acetate Gonadotropin Releasing Hormone (GnRH) Analogue

Action and Clinical

Nafarelin is an agonistic analogue of the gonadotropin releasing hormone (GnRH). Given as a single intranasal dose, nafarelin stimulates release of the pituitary gonadotropins, LH and FSH, with consequent increase of ovarian steroidogenesis. Repeated intranasal dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration of 200 g, as a nasal spray, leads to decreased secretion of gonadal steroids by about 4 weeks. Consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent.

Pharmacokinetics: Nafarelin is rapidly absorbed from the nasal mucosa into the systemic circulation after intranasal administration. The relative bioavailability of intranasally administered nafarelin averaged 2.8% (range 1.2 to 5.6%). This was determined by comparing nafarelin AUC values after a single 400 g intranasal dose and a 25 g i.v. dose and adjusting for the lower i.v. dose administered. The low relative bioavailability results from the drug not being well absorbed by the nasal mucosa. Maximum plasma concentrations are achieved 10 to 40 minutes after dosing. Following a single intranasal dose of 200 g base, the observed average peak concentration of nafarelin is 0.6 ng/mL, whereas following a single dose of 400 g base, the observed average peak concentration is 1.8 ng/mL (range 1.52 to 2.0 ng/mL). The average serum half-life of nafarelin following intranasal administration is 3 hours (range 2 to 4 hours).

The effect of rhinitis or a topical decongestant on intranasally administered Synarel has not yet been determined with the presently available formulation.

Clinical Use: In controlled clinical studies, nafarelin at doses of 400 and 800 g/day for 6 months was shown to relieve the clinical symptoms of endometriosis (pelvic pain, dysmenorrhea, and dyspareunia) and to reduce the size of endometrial implants as determined by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time. Laparoscopic staging of endometriosis did not necessarily correlate with severity of symptoms.

In 73 patients, Synarel 400 g daily induced amenorrhea in approximately 65%, 80% and 90% of the patients after 60, 90 and 120 days, respectively. Most of the remaining patients reported episodes of only light bleeding or spotting. In the first, second and third post-treatment months normal menstrual cycles resumed in 4%, 82% and 100%, respectively, of those patients who did not become pregnant.

The distribution of patients, treated with 400 g/day, by symptom severity at admission, end of treatment and 6 months after treatment.

Indications And Clinical Uses:

For hormonal management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with nafarelin for the management of endometriosis has been limited to women 18 years of age and older and treated for 6 months. There is no evidence that pregnancy rates are enhanced or adversely affected by its use.

Contra-Indications:

ContraindicationsShould not be administered to patients who: are hypersensitive to GnRH, GnRH agonist analogues or any of the excipients in this product; have undiagnosed abnormal vaginal bleeding; are pregnant or who may become pregnant while receiving the drug (see Warnings). It is not known whether nafarelin causes fetal abnormalities in humans; are breast feeding (see Warnings).WarningWarnings

Warnings in Clinical States:

General: Isolated cases of short-term worsening of signs and symptoms or enlargement of ovarian cysts have been reported during initiation of nafarelin therapy: they are sometimes, but not necessarily, associated with a stimulation of the pituitary gland and an initial increase in the levels of circulating gonadal hormones.

Worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.

Pregnancy and Lactation: Safe use of nafarelin in pregnancy has not been established clinically. Before starting treatment, pregnancy must be excluded.

When used regularly at the recommended dose, nafarelin usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking nafarelin, particularly if patients miss successive drug 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. There is no experience with nafarelin in pregnant women.

It is not known whether or to what extent nafarelin is excreted into human breast milk. The effects, if any, on the breast-fed child have not been determined and therefore, nafarelin should not be used in breast feeding women.

Children: The safety and effectiveness in children have not been established and therefore, nafarelin should not be used.

Precautions:

Information for the Patient: An information pamphlet for patients is included with the product and should be read carefully before initiating treatment with nafarelin. Patients should be made aware of the following information.

Menstruation: Since menstruation should stop with effective doses of nafarelin, the patient should notify her physician, if regular menstruation persists. Patients missing successive doses of the drug may experience break through vaginal bleeding.

Pregnancy and Lactation: Patients should not use nafarelin if they are pregnant, breast-feeding, have undiagnosed abnormal vaginal bleeding or are allergic to any of the ingredients in the product.

Use in Women of Childbearing Potential: 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 nafarelin, ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.

Adverse Events: Adverse events associated with the hypoestrogenic state induced by nafarelin, occurred in clinical studies. The most frequently reported adverse events were hot flashes (90%), decrease in libido (22%), headache (19%), vaginal dryness (19%), emotional lability (15%), acne (13%), myalgia (10%) and reduction in breast size (10%). Estrogen levels returned to normal after treatment was discontinued with resolution of the hypoestrogenic effects. Nasal irritation occurred in about 10% of all patients who used intranasal nafarelin.

Bone Density: The induced hypoestrogenic state caused by nafarelin results in a small loss in bone density over the course of treatment, some of which may not be reversible. During one 6-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, nafarelin therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy is instituted. Repeated courses of treatment with gonadotropin releasing hormone analogues are not advisable in patients with major risk factors for loss of bone mineral content.

Retreatment: The safety of retreatment as well as of treatment beyond 6 months with nafarelin has not yet been established.

Drug Interactions:

No pharmacokinetic drug interaction studies have been conducted with nafarelin. However, because nafarelin is a peptide that is primarily degraded by peptidases and not by cytochrome P-450 enzymes, and because the drug is only about 80% bound to plasma proteins at 4°C, drug interactions would not be expected to occur.

Patients with intercurrent rhinitis should consult with their physician before the use of a topical nasal decongestant. If the use of a topical nasal decongestant is required during treatment with nafarelin, the decongestant must be used at least 30 minutes after dosing to decrease the possibility of reducing drug absorption. The effect of rhinitis or a topical decongestant on nafarelin absorption by the nasal mucosa has not yet been determined.

Diagnostic Interference: Administration of nafarelin in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 8 weeks after treatment is discontinued. Diagnostic tests of pituitary-gonadal function conducted during the treatment and within 8 weeks after discontinuation of nafarelin therapy may therefore be misleading.

Fertility Studies: Use of nafarelin in human pregnancy has not been studied. After 6 months of therapy, 56 patients, who were treated with 400 g/day, desired and attempted pregnancy. By the end of 18 months post treatment, 17 (30%) patients became pregnant. In the 800 g/day group, out of 48 patients attempting pregnancy, 25 of them (52%) became pregnant within 18 months post treatment. Full term delivery occurred in 82% and 68% of patients in the 400 and 800 g/day groups respectively. All newborns were normal except for one male baby who had hydrocele. The mother of the baby was in the 400 g/day group.

The serum concentration of gonadotropins and estradiol returned promptly to normal after cessation of therapy.

Mutagenicity and Carcinogenicity: As seen with other GnRH agonists, high parenteral doses (up to 100 g/kg/day in mice for 18 months and 500 g/kg/day in rats for 24 months) induced hyperplasia and/or neoplasia (without metastasis) of endocrine organs including the pituitary (adenoma/carcinoma). Rodents are particularly sensitive to hormonal stimulation when tested for tumorigenicity. No evidence of tumorigenicity has been reported in monkeys or man. No indication of a mutagenic potential for nafarelin has been reported.

Adverse Reactions:

As would be expected with a drug which lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.

Controlled studies included 203 evaluable women (mean age 32 years) treated on average for 170 days with nafarelin 400 g/day. The adverse reactions most frequently reported and thought to be drug related are listed below (% incidence (n=203)).

CNS: headache 19%, emotional lability 15%, nervousness 9%, insomnia 8%, depression 2%, dizziness 1%, vertigo 1%, incoordination 0.5%, neurosis 0.5%, increased sweating 0.5%.

Skin and Appendages: acne 13%, breast atrophy 10%, seborrhea 8%, hirsutism 2%, dry skin 2%, alopecia 0.5%, chloasma 0.5%, gynecomastia 0.5%, herpes simplex 0.5%, maculopapular rash 0.5%.

Urogenital: vaginal dryness 19%, dyspareunia 1%, menstrual disorder 0.5%, cystitis 0.5%, dysuria 0.5%, urinary incontinence 0.5%, vaginal hemorrhage 0.5%.

Metabolic and Nutritional Disorders: weight gain 8%, edema 8%, weight loss 1%.

Musculoskeletal: myalgia 10%, arthralgia 1%, myasthenia 0.5%.

Digestive: nausea 7%, gastrointestinal fullness 5%, increased appetite 1%, anorexia 1%, constipation 0.5%, diarrhea 0.5%, gastritis 0.5%, vomiting 0.5%.

Respiratory: rhinitis 10%, epistaxis 1%, dry nose 0.5%, sinusitis 0.5%, voice alteration 0.5%.

Special Senses: taste perversion 3%, conjunctivitis 1%, ear pain 0.5%, eye pain 0.5%.

Body as a Whole: asthenia 1%, mucous membrane disorder 0.5%.

Cardiovascular: hot flashes 90.0%, palpitation 0.5%.

Others: breast pain 3%, decreased libido 22%, increased libido 1%.

Changes in Bone Density: After 6 months of treatment, vertebral trabecular bone density and total vertebral bone mass, measured by quantitative computed tomography (QCT), decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment levels. There was partial recovery of bone density, when assessed 6 months after end of treatment, the average trabecular bone density and total bone mass were 4.9% and 3.3% less than the pretreatment levels, respectively. Total vertebral bone mass, measured by dual photon absorptiometry (DPA), decreased by a mean of 5.9% at the end of treatment. Mean total vertebral mass, re-examined by DPA 6 months after completion of treatment, was 1.4% below pretreatment levels. There was little, if any, decrease in the mineral content in compact bone of the distal radius and second metacarpal. Use of nafarelin for longer than the recommended 6 months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Changes in Laboratory Values: Plasma Enzymes: After 6 months of therapy with 400 g/day of nafarelin, elevations in AST outside the normal range were observed in 5 (3%) of 180 patients with normal baseline values. Post- treatment evaluations were available for 4 of these patients: the level of AST was within the normal range. For ALT, 2 (3 %) of 68 patients with normal baseline had increases outside the normal range. 1 patient, for which data are available, returned to normal during the post-treatment observation. For alkaline phosphatase, 10 (5%) out of 182 patients with normal baseline level had increases outside the normal range at the end of treatment. Post-treatment evaluations were available for 8 of these patients: 4 patients were within the normal range, the other 4 patients were above the normal range but this was not considered clinically significant.

Lipids: At enrollment, 9% of the patients receiving nafarelin 400 g/day had total cholesterol values above 250 mg/dL. These patients also had cholesterol values above 250 mg/dL at the end of treatment.

Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in the nafarelin group, had post-treatment values above 250 mg/dL.

The mean (±SEM) pretreatment values for total cholesterol from all nafarelin patients were 191.8 (4.3) mg/dL. At the end of the treatment period, the mean values for total cholesterol from all patients in the nafarelin group were 204.5 (4.8) mg/dL. The increase from the pretreatment value was statistically significant (p<0.05).

Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients who received nafarelin.

Following completion of treatment, no patients receiving nafarelin had abnormally low HDL cholesterol fractions (less than 30 mg/dL) and none of the patients receiving nafarelin had abnormally high LDL cholesterol fractions (greater than 190 mg/dL). There was no increase in the LDL/HDL ratio in patients receiving nafarelin.

Other Changes: In comparative studies, the following changes were seen in approximately 10% to 15% of patients. Nafarelin treatment was associated with elevations of plasma phosphorus and eosinophil counts, and decreases in serum calcium and WBC counts.

Symptoms And Treatment Of Overdose:

In experimental animals a single s.c. administration of up to 60 times the recommended human dose (expressed on a g/kg basis not adjusted for bioavailability) had no adverse effects. Orally administered nafarelin is subject to enzymatic degradation in the gastrointestinal tract and is therefore inactive. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogues.

Dosage And Administration:

For the management of endometriosis, the recommended daily dose is 400 g. This is achieved by 1 spray (200 g of nafarelin free base) into 1 nostril in the morning and 1 spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle.

In an occasional patient, the 400 g daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose may be increased to 800 g daily. The 800 g dose is administered as 1 spray into each nostril in the morning (a total of 2 sprays) and again in the evening.

The recommended duration of administration is 6 months. The safety of retreatment as well as of treatment beyond 6 months with nafarelin has not yet been established. If the symptoms of endometriosis recur after a course of therapy, and further treatment is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.

If the use of a topical nasal decongestant is necessary during treatment with this product, the decongestant should not be used until at least 30 minutes after nafarelin dosing (see Precautions).

At 400 g/day, a 8 mL bottle of nafarelin provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy.

Availability And Storage:

Each mL of nasal solution contains: nafarelin acetate 2 mg (as nafarelin base). Nonmedicinal ingredients: benzalkonium chloride, glacial acetic acid, hydrochloric acid or sodium hydroxide, sorbitol and purified water. Bottles of 8 mL. Each bottle is supplied with a metered spray pump. A dust cover and a leaflet of patient instructions are also included.

After priming the pump unit, each actuation of the unit delivers approximately 100 L of the metered droplet spray containing approximately 200 g nafarelin base. The contents of one 8 mL spray bottle is intended to deliver at least 60 sprays. Store upright between 15 and 25°C. Protect from light and freezing.

SYNAREL® Searle Nafarelin Acetate Gonadotropin Releasing Hormone (GnRH) Analogue

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