Pfizer Canada Inc Date of Preparation: 17,300 Trans-Canada Highway 24 September 2003 Kirkland, Quebec H9J 2M5 Control No. 086876 * TM G.D. Searle LLC Pfizer Canada Inc, Licensee
(c)
Pfizer Canada Inc 2003
Distributed by: Ferring Pharmaceuticals Toronto, Ontario
(nafarelin acetate) 2 mg/mL nasal solution (as nafarelin base)
Gonadotropin releasing hormone (GnRH) analogue
ACTION
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 ug, 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 - 5.6%). This was determined by comparing nafarelin AUC values after a single 400 ug intranasal dose and a 25 ug IV dose and adjusting for the lower IV dose administered. The low relative bioavailability results from the drug not being well absorbed by the nasal mucosa. Maximum plasma concentrations are achieved 10-40 minutes after dosing. Following a single intranasal dose of 200 ug base, the observed average peak concentration of nafarelin is 0.6 ng/mL, whereas following a single dose of 400 ug base, the observed average peak concentration is 1.8 ng/mL (range 1.52-
ng/mL). The average serum half-life of nafarelin following intranasal administration is 3 hours (range 2-4 hours).
The effect of rhinitis or a topical decongestant on intranasally administered Synarel (nafarelin acetate) has not yet been determined with the presently available formulation. Clinical Use: In controlled clinical studies, Synarel at doses of 400 and 800 ug/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 ug 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 ug/day, by symptom severity at admission, end of treatment and 6 months after treatment is as follows:
SYMPTOM SEVERITY SCORE
| N | 0 NONE | 1 - 2 MILD | 3 - 5 MODERATE | 6 - 9 SEVERE | |
| At Admission End of treatment 6 months after treatment | 73 73 73 | 6 (8%) 44 (60%) 37 (51%) | 26 (36%) 23 (32%) 24 (33%) | 28 (38%) 5 (7%) 12 (16%) | 13 (18%) 1 (1%) -- --- |
INDICATIONS
Synarel (nafarelin acetate) is indicated for hormonal management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with Synarel 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 the use of Synarel.
Synarel (nafarelin acetate) should not be administered to patients who:
Are hypersensitive to GnRH, GnRH agonist analogues or any of the excipients in Synarel;
Have undiagnosed abnormal vaginal bleeding;
Are pregnant or who may become pregnant while receiving the drug (see WARNINGS).
It is not known whether Synarel causes fetal abnormalities in humans. (see
for findings in animals).
Are breast feeding (see WARNINGS).
Isolated cases of short-term worsening of signs and symptoms or enlargement of ovarian cysts have been reported during initiation of nafarelin acetate 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. 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, worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.
Safe use of Synarel (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 ensured, however, by taking Synarel, particularly if patients miss successive drug doses. Therefore, PATIENTS SHOULD USE NONHORMONAL METHODS OF
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 informed of the potential risk to fetal development. There is no experience with Synarel 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 Synarel should not be used in breast feeding women.
The safety and effectiveness of Synarel in children have not been established and therefore Synarel should not be used.
An information pamphlet for patients is included with the product and should be read carefully before initiating treatment with Synarel (nafarelin acetate). Patients should be made aware of the following information:
Since menstruation should stop with effective doses of Synarel, the patient should notify her physician, if regular menstruation persists. Patients missing successive doses of Synarel may experience break through vaginal bleeding.
Patients should not use Synarel if they are pregnant or suspected pregnant, are breast-feeding, have undiagnosed abnormal vaginal bleeding or are allergic to any of the ingredients in Synarel. The patient must be informed of the potential risk to fetal development.
Safe use of the drug in pregnancy has not been established clinically. Therefore,
. Patients should be advised that if they miss successive doses of Synarel, ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician. The patient must be informed of the potential risk to fetal development.
Adverse events associated with the hypoestrogenic state induced by Synarel, 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 Synarel, 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, Synarel therapy 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 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 Synarel has not yet been established, and therefore retreatment cannot be recommended.
No pharmacokinetic drug interaction studies have been conducted with Synarel. However, because nafarelin acetate 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 4EC, 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 Synarel, the decongestant must be used at least 30 minutes after Synarel dosing to decrease the possibility of reducing drug absorption. The effect of rhinitis or a topical decongestant on Synarel absorption by the nasal mucosa has not yet been determined. Sneezing during or immediately after dosing may impair absorption of nafarelin acetate. If sneezing occurs upon administration, repeating the dose may be advisable.
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.
Use of Synarel in human pregnancy has not been studied. After 6 months of therapy with Synarel, 56 patients, who were treated with 400 ug/day, desired and attempted pregnancy. By the end of 18 months post treatment, 17 (30%) patients became pregnant. In the 800 ug/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 ug/day groups respectively. All newborns were normal except for one male baby who had hydrocele. The mother of the baby was in the 400 ug/day group. The serum concentration of gonadotropins and estradiol returned promptly to normal after cessation of therapy.
As seen with other GnRH agonists, high parenteral doses (up to 100 ug/kg/day in mice for 18 months and 500 ug/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.
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 Synarel (nafarelin acetate) 400 ug/day. The adverse reactions most frequently reported and thought to be drug related are tabulated below.
ADVERSE REACTION %INCIDENCE (n=203)
Central Nervous System
Headache Emotional lability Nervousness Insomnia Depression Dizziness
Vertigo Incoordination Neurosis
Increased sweating
0.5
0.5
0.5
Skin and Appendages
Acne
Breast atrophy Seborrhea Hirsutism
Dry skin Alopecia Chloasma Gynecomastia Herpes Simplex
Maculopapular rash
0.5
0.5
0.5
0.5
0.5
Urogenital System Vaginal dryness Dyspareunia Menstrual disorder Cystitis
Dysuria
Urinary incontinence Vaginal Hemorrhage
0.5
0.5
0.5
0.5
0.5
Metabolic and nutritional disorders
Weight gain 8
Edema 8
Weight loss 1
Musculo-Skeletal System
Myalgia Arthralgia Myasthenia
0.5
Digestive System
Nausea
ADVERSE REACTION %INCIDENCE (n=203)
Gastrointestinal fullness
Increased appetite Anorexia Constipation Diarrhea
Gastritis Vomiting
0.5
0.5
0.5
0.5
Respiratory System Rhinitis Epistaxis
Dry nose Sinusitis
Voice alteration
0.5
0.5
0.5
Special Senses Taste perversion Conjunctivitis Ear pain
Eye pain
0.5
0.5
Body as a whole
Asthenia
Mucous membrane disorder
0.5
Cardiovascular System Hot flashes Palpitaton
90.0
0.5
Others
Breast pain 3
Decreased libido 22
Increased libido 1
In approximately 2% of adult patients, symptoms suggestive of drug sensitivity, such as chest pain, pruritus, rash, shortness of breath and urticaria have occurred. In other clinical trials and post-marketing experience, paresthesia and blood pressure changes were also reported. In very rare instances, uterine hemorrhage can occur.
Changes in Bone Density:
After six months of Synarel 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 six 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 Synarel for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.
There are no data in changes in bone density in children.
Changes in Laboratory Values
Plasma enzymes:
After 6 months of therapy with 400 ug/day of Synarel, elevations in SGOT 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 SGOT was within the normal range. For SGPT, 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 Synarel 400 ug/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 Synarel group, had post-treatment values above 250 mg/dL. The mean (+-SEM) pretreatment values for total cholesterol from all Synarel 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 Synarel 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 Synarel. Following completion of treatment, no patients receiving Synarel had abnormally low HDL cholesterol fractions (less than 30 mg/dL) and none of the patients receiving Synarel had abnormally high LDL cholesterol fractions (greater than 190 mg/dL). There was no increase in the LDL/HDL ratio in patients receiving Synarel.
Other Changes:
In comparative studies, the following changes were seen in approximately 10% to 15% of patients. Synarel treatment was associated with elevations of plasma phosphorous and eosinophil counts, and decreases in serum calcium and WBC counts.
In experimental animals a single subcutaneous administration of up to 60 times the recommended human dose (expressed on a ug/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. There is no clinical experience with overdosage of nafarelin acetate. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogues.
For the management of endometriosis, the recommended daily dose of Synarel (nafarelin acetate) is 400 ug. This is achieved by one spray (200 ug of nafarelin free base) into one nostril in the morning and one 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 ug daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of Synarel may be increased to 800 ug daily. The 800 ug dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. The recommended duration of administration is six 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 with Synarel 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 Synarel, the decongestant should not be used until at least 30 minutes after Synarel dosing (see PRECAUTIONS). At 400 ug/day, an 8 mL bottle of Synarel provides a 30 day supply (about 60 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy.
Chemical Name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-
L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl- L-arginyl-L-prolylglycinamide acetate
Molecular Formula: C66 H83 N17013. x C2 H4 02. y H2 0 (1< x <2; 2< y<8)
1322.51 (anhydrous free decapeptide)
Nafarelin acetate is a fine white to off-white amorphous powder. It is slightly soluble in water, very slightly soluble in 0.02M phosphate buffer (pH 7.58), methanol and ethanol and practically insoluble in acetonitrite and dichloromethane. The apparent pKa's of nafarelin acetate have been determined spectrophotometrically to be 5.93 and 9.92, corresponding to the histidyl and the tyrosyl groups, respectively. The expected pKa of the arginyl group is 12.48, which has not been independently measured due to experimental limitations.
Each 8mL bottle of Synarel (nafarelin acetate) contains nafarelin acetate nasal solution 2 mg/mL (as nafarelin base), in a solution of sorbitol, benzalkonium chloride, glacial acetic acid, sodium hydroxide or hydrochloric acid to adjust pH, and purified water. 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 for Synarel, each actuation of the unit delivers approximately 100 uL of the metered droplet spray containing approximately 200 ug nafarelin base. The contents of one 8mL spray bottle is intended to deliver at least 60 sprays. Store upright between 15 - 25oC. Protect from light and freezing.