Nafarelin

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Abstract
Nafarelin, a synthetic agonist of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH); gonadorelin] appears likely to join the other GnRH analogues currently used in a range of conditions reliant on gonadotrophins or sex hormones. With repeated administration, the pituitary becomes desensitised, and gonadotrophin release, and therefore sex hormone synthesis, are inhibited. Nafarelin has proved to be comparable to danazol in the management of women with endometriosis, with fewer potentially harmful adverse effects. Nafarelin has also been used effectively in in vitro fertilisation programmes, and in hirsute women and those with uterine leiomyoma, particularly to induce preoperative fibroid shrinkage. The drug shrinks hypertrophic tissue in men with benign prostatic hyperplasia, although treatment would need to be maintained indefinitely and therefore should probably be reserved for those unsuitable for prostatectomy. Preliminary data suggest that nafarelin is equivalent to diethylstilbestrol (stilboestrol) in terms of disease-free survival in men with prostate cancer. As a reliable method of contraception, nafarelin gives unpredictable results in men and the promising results in women may be offset by hypoestrogenic side effects. Nafarelin may join other GnRH agonists which are now routinely used in the management of children with central or combined precocious puberty. Nafarelin is readily and rapidly absorbed following intranasal delivery, and is protected to some extent from enzymatic degradation. The resultant relatively long elimination half-life allows once-or twice-daily administration. Estrogen depletion accounts for the most common side effects associated with nafarelin, including hot flushes and vaginal dryness, which are mild and tolerable in most patients. Reversible resorption of trabecular bone can occur during nafarelin therapy, perhaps necessitating cyclical treatment to enable bone mass to recover. Nafarelin, therefore, looks likely to find a role in the treatment of women with endometriosis, and results achieved in other conditions dependent on the pituitary-gonadal axis are promising. Nafarelin is a synthetic analogue of GnRH and is about 200 times more potent than the endogenous peptide. It stimulates the release of the gonadotrophins luteinising hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary, but this effect gradually wanes with multiple doses as the pituitary becomes desensitised, possibly from down-regulation of receptors. Single intranasal or subcutaneous doses of nafarelin elevate serum LH and FSH levels in both sexes. The magnitude and rate of gonadotrophin release are greatest in women during the late follicular and luteal phases of the menstrual cycle. After 2 or 3 days of daily nafarelin administration, the pituitary becomes refractory, and LH and FSH release is inhibited within 10 days. Intermittent intramuscular administration of testosterone enanthate 200mg enhances gonadotrophin suppression in healthy men. Although variable between individuals, pituitary desensitisation is proportional to nafarelin dosage. Like other GnRH agonists, nafarelin also appears to reduce the biological activity of LH. In men, serum testosterone levels initially increase after subcutaneous administration of nafarelin 10 to 200μg, and then gradually decline to below baseline after 10 days. Spermatogenesis is suppressed by up to 92% during treatment with nafarelin 200 or 400 μg/day subcutaneously plus concomitant fortnightly testosterone enanthate 200mg intramuscularly, although azoospermia is rare and unpredictable. Sperm counts normalise within 16 weeks of stopping nafarelin. In women, single intranasal doses of 125 or 500μg, and 1, 5 or 100μg subcutaneously, increase mean serum estradiol levels by 2 to 4 times in a dose-proportional manner. The greatest increases occur when nafarelin is given during the early follicular phase of the cycle. Peak estradiol release occurs after 2 weeks’ administration, and then steadily decreases to pretreatment levels or lower. Despite variable responses, mean progesterone levels increase initially and then fall to pretreatment values after 10 days of daily nafarelin administration during the luteal phase. Levels of progesterone indicative of ovulation have been detected in fewer than 18% of cycles during intranasal delivery of nafarelin acetate 125 or 250 μg/day for 3 to 6 months. With a twice-daily dosage of nafarelin 500μg, progesterone release and ovarian testosterone synthesis appear to be completely inhibited. Single doses of nafarelin 1, 5, 20 or 100μg given subcutaneously during the early follicular phase lengthen the mean menstrual cycle duration and postpone ovulation. Amenorrhoea and oligomenorrhoea are common during 3 to 6 months’ intranasal administration of nafarelin acetate 125 or 250 μg/day, with ovulatory menses re-established between 28 and 48 days after discontinuing the drug. To summarise, single doses of nafarelin stimulate the release of LH and FSH, which provokes sex steroid production. With repeated administration, the pituitary becomes desensitised and gonadotrophin release is inhibited. The biological activity of LH may also be altered. Consequently, follicle maturation, ovulation and luteinisation are usually prevented in women, resulting in reduced estrogen and progesterone synthesis, and in men testosterone production and spermatogenesis are inhibited. Nafarelin is a decapeptide and therefore susceptible to gastrointestinal peptidase degradation, making it unsuitable for oral administration. Mean peak nafarelin plasma concentrations (Cmax), achieved within 5 to 60 minutes, were 13.6 μg/L after a single subcutaneous dose of nafarelin 400μg, and 0.1, 0.35 and 1.59 μg/L following intranasal doses of 84, 206 and 336μg, respectively, in healthy men and women. Intranasal absorption is enhanced by using more concentrated solutions of nafarelin and by including sodium glycocholate in the formulation. The mean bioavailability of nafarelin following intranasal administration is about 4 to 21%. Nafarelin is rapidly and extensively distributed to extravascular tissue in animals, despite about 80% being bound to plasma proteins in vitro, principally to albumin. Six metabolites, together with the parent compound, accounted for 36% of the total dose and 85% of urinary radioactivity after a subcutaneous dose of 14C-nafarelin 216μg in 3 healthy men. The major metabolites, each representing about 20% of the total urinary activity, were the (5–10) hexapeptide amide and naphthylalanine. About half of the total radioactivity was recovered in the urine and 19 to 44% in the faeces over 7 days. The elimination half-life (t½) is about 2 or 3 hours following intranasal delivery of nafarelin and 4 or 5 hours after subcutaneous administration, longer than the t½ of 30 minutes for native GnRH as a result of nafarelin being more resistant to peptidase degradation. A plasma concentration as low as 50 ng/L is needed for nafarelin to elicit a response at the pituitary in some individuals. Peak gonadotrophin levels in response to single doses of nafarelin lagged about 2 to 3 hours behind the Cmax of the drug. Nafarelin has been used successfully in both sexes in a range of conditions dependent on the pituitary-gonadal axis. In open small-scale trials, nafarelin 20 to 1000 μg/day administered subcutaneously or intranasally reduced the symptoms and signs of endometriosis within 3 months. More importantly, 2 well-designed comparative studies each involving around 200 patients revealed reductions in American Fertility Society severity scores of 43 to 49%, and similar improvements in symptom relief and ectopic tissue eradication in women receiving nafarelin 200 or 400μg twice daily intranasally, or danazol 400mg twice daily or 200mg 3 times daily orally for 6 months. Over 70% of women in 1 study were symptom-free or had only mild symptoms 6 months after stopping either drug. In 10 women with uterine leiomyoma (fibroids), intranasal nafarelin 800 μg/day reduced uterine volume by 57% (mean) after 6 months, corresponding to a decrease in estradiol levels. Shrinkage of fibroids was variable, but nevertheless facilitated surgical excision. Since myomas increased in size again once nafarelin was stopped and ovarian estrogen synthesis restored, myomectomy following preoperative shrinkage with nafarelin may represent the optimum use for the drug in this setting. Inhibition of ovarian testosterone production by intranasal administration of nafarelin 500μg twice daily for 6 months resulted in a clinical improvement in 6 hirsute women, including 4 with polycystic ovary syndrome. The effects of the lower dose of 200μg twice daily on ovarian volume and number of follicles in another 11 patients with polycystic ovary syndrome were inconsistent, and only modest improvements were achieved in the hirsutism of 7 of the women. Nafarelin 400 μg/day intranasally successfully suppressed ovarian function in 53 women undergoing in vitro fertilisation. Subsequent stimulation of follicular development with menotropins [human menopausal gonadotrophin (HMG)] led to adequate follicle numbers, and 33 patients progressed to embryo transfer; 10 pregnancies resulted. In 9 men with benign prostatic hyperplasia, daily subcutaneous injections of nafarelin acetate 400μg suppressed circulating testosterone below castrate levels (about 1 nmol/L) and decreased mean prostate size by 25% after 4 months. Obstructive and, to a lesser extent, irritative symptoms were relieved, but urinary flow rate improved to a clinically significant degree in only 3 men. Virtually all the hypertrophic tissue returned when nafarelin was stopped. Thus, continued treatment would be necessary to maintain remission, and should be reserved for those patients unsuitable for prostatectomy. Although other GnRH agonists are now accepted treatment for men with stage D2 prostatic carcinoma, data regarding the use of nafarelin in such patients are limited. Seven of 9 men treated with daily subcutaneous injections of nafarelin 400μg responded according to National Prostatic Cancer Project criteria, with a median time to disease progression of about 16 months and a median survival time of over 2 years. In a comparative study, castrate testosterone levels were achieved in 60 recipients of nafarelin acetate 300μg intranasally twice daily and in 65 men receiving diethylstilbestrol 1mg orally 3 times daily, with similar disease-free survival rates of 84% and 70%, respectively, after 6 months’ follow-up. The contraceptive potential of 3 to 6 months of intranasal administration of nafarelin acetate 125 or 250μg once daily has been evaluated in groups of 8 to 25 healthy women. Overall, pregnancy was prevented during a total of 281 months when nafarelin was the only contraceptive method used by 77 women. Presumed ovulation was inhibited in over 81% of cycles during administration of the lower dose, and in at least 97% with the higher dose. Endometrial biopsy specimens generally revealed atrophic or weakly proliferative tissue. Bleeding patterns were disrupted and unpredictable during nafarelin treatment, with amenorrhoea present in 40 to 60% of women receiving 125 μg/day and in 10 to 87% with twice this dosage. Ovulatory menses were usually re-established 30 to 45 days after discontinuing nafarelin. Nafarelin 400, 800, 1200 or 1600 μg/day, given as a single daily intranasal dose or in 3 divided doses, slowed the linear growth rate of small groups of children with central or combined precocious puberty by 30 to 50%. Suppression of secondary sexual characteristics was inconsistent. The reduction in circulating estrogens accounts for the most frequently reported adverse effects of nafarelin. Hot flushes, usually mild and tolerable, were experienced by 38 to 65% of women receiving nafarelin acetate 250 μg/day intranasally and by over 90% with higher doses. Women also reported reduced libido and vaginal dryness. In 10 men with benign prostatic hyperplasia receiving nafarelin 400 μg/day subcutaneously, hot flushes and impotence were universal. These troublesome, but not dangerous, unwanted effects occurred more frequently with nafarelin than with danazol in women receiving treatment for endometriosis. However, nafarelin was associated with a lower incidence of weight gain, oedema, myalgia and elevated serum liver enzymes than danazol and, unlike danazol, was not associated with undesirable changes in serum lipids. Trabecular bone mineral density decreased by 6 to 11% over a 6-month period of therapy with nafarelin 400 or 600 μg/day, caused by increased bone resorption associated with lower estrogen levels. Most of this lost bone mass was recuperated on nafarelin withdrawal, and appeared to be minimised by concomitant hormone replacement therapy. Nasal irritation has occasionally been reported following intranasal administration of nafarelin, as has headache and emotional lability. Disease ‘flare’ associated with the short term stimulation of gonadotrophin and sex hormone release at the beginning of therapy does not appear to be common. Since nafarelin is inactive if given orally, it is routinely administered intranasally or occasionally subcutaneously. Twice daily intranasal application of 200 to 500μg has been effective in women with endometriosis, leiomyoma or hirsutism, and in men with prostatic carcinoma. Subcutaneous injections of 400 μg/day have also been used in prostate cancer patients and in men with benign prostatic hypertrophy. In female contraception, intranasal administration of nafarelin acetate 250 μg/day prevented ovulation almost completely, whereas a less predictable response was obtained with 125μg daily. Intranasal dosages ranging from 400 to 1600μg — but usually 25 μg/kg given as a single daily dose or in 3 divided doses — have been employed with generally favourable results in children with central or combined precocious puberty.