Lutrepulse (Gonadorelin)

LUTREPULSE™

Ferring

Gonadorelin Acetate

Ovulatory Agent

Action And Clinical Pharmacology: Gonadorelin is a synthetic decapeptide that has the same amino acid sequence as endogenous gonadotropin-releasing hormone (GnRH) synthesized in the human hypothalamus and in various neurons terminating in the hypothalamus. Its pharmacological and toxicological profile is therefore identical to that of endogenous GnRH.

Under physiologic conditions, GnRH is released by the hypothalamus in a pulsatile fashion. The primary effect of GnRH is the synthesis and release of luteinizing hormone (LH) in the anterior pituitary gland. GnRH also stimulates the synthesis and release of follicle stimulating hormone (FSH), but this effect is less pronounced. LH and FSH subsequently stimulate the gonads to produce steroids which are instrumental in regulating reproductive hormonal status. Unlike human menopausal gonadotropin (hMG) which supplies pituitary hormones, pulsatile administration of gonadorelin replaces defective hypothalamic secretion of GnRH. Gonadorelin for pulsatile injection approximates the natural hormonal secretory pattern, causing pulsatile release of pituitary gonadotropins. Accordingly, gonadorelin for pulsatile injection is useful in treating conditions of infertility caused by defective GnRH stimulation from the hypothalamus.

The following information summarizes clinical efficacy of gonadorelin administered by pulsatile i.v. or s.c. injection to patients with primary hypothalamic amenorrhea.

In 48 patients with primary hypothalamic amenorrhea (HA) 94% (45/48) patients ovulated and 58% (25/43) patients became pregnant (5 patients did not desire pregnancy).

Treatment was successful even in those patients who failed past attempts at ovulation induction by other methods.

Following i.v. or s.c. injection of GnRH into normal subjects and/or hypogonadotropic patients, plasma GnRH concentrations rapidly declined with initial and terminal half-lives of 2 to 10 min and 10 to 40 min, respectively. In these studies, high clearance values (500 to 1 500 L/day) and low volumes of distribution (9 to 15 L) were calculated. The pharmacokinetics of GnRH in normal subjects and in hypogonadotropic patients were similar. GnRH was rapidly metabolized to various biologically inactive peptide fragments which are readily excreted in urine. Renal failure, but not hepatic disease, prolonged the half-life and reduced the clearance of GnRH.

aneGonadorelin alone is therefore able to maintain the corpus luteum during pregnancy.

Indications And Clinical Uses: For the induction of ovulation in women with primary hypothalamic amenorrhea.

Differential Diagnosis: Proper diagnosis is critical for successful treatment with gonadorelin. It must be established that hypothalamic amenorrhea or hypogonadism is, in fact, due to a deficiency in quantity or pulsing of endogenous GnRH. The diagnosis of hypothalamic amenorrhea or hypogonadism is based on the exclusion of other causes of the dysfunction, since there is currently no practical technique to directly assess hypothalamic function. Prior to initiation of therapy with gonadorelin the physician should rule out disorders (other than abnormalities of GnRH secretion), that can cause amenorrhea and involve most often general health, reproductive organs, CNS, anterior pituitary, thyroid, adrenals or other endocrine or metabolic disorders.

Contra-Indications: Women with any condition that could be exacerbated by pregnancy. For example, pituitary prolactinoma should be considered one such condition. Additionally, any history of sensitivity to gonadorelin or any component of this product is a contraindication.

Patients who have ovarian cysts should not receive gonadorelin.

Gonadorelin is intended to initiate events including the production of reproductive hormones (e.g., estrogens and progesterone). Therefore, any condition that may be worsened by reproductive hormones, such as a hormonally-dependent tumor, is a contraindication to the use of gonadorelin.

Manufacturers’ Warnings In Clinical States: Therapy with gonadorelin should be conducted by physicians familiar with pulsatile GnRH delivery and the clinical ramifications of ovulation induction. While there have been few cases of hyperstimulation.

Multiple pregnancy is a possibility that can be minimized by careful attention to the recommended doses and ultrasonographic monitoring of the ovarian response to therapy. Following a baseline pelvic ultrasound, follow-up studies should be conducted at a minimum on day 7 and day 14 of therapy.

As with any parenteral medication, scrupulous attention to asepsis is important. The infusion area must be monitored as with all indwelling parenteral approaches.

Precautions: General: Ovarian hyperstimulation has been reported. This may be related to pulse dosage or concomitant use of other ovulation stimulators. Hyperstimulation may be a greater risk in patients where spontaneous variations in endogenous GnRH secretion occur. Multiple follicle development, multiple pregnancy and spontaneous termination of pregnancy have been reported. Multiple pregnancy can be minimized by appropriate monitoring of follicle formation; nonetheless, the patient and her partner should be advised of the frequency (12%) and potential risks of multiple pregnancy before starting treatment.

Ovarian hyperstimulation, a syndrome of sudden ovarian enlargement, ascites with or without pain, and/or pleural effusion, is rare with pulsatile GnRH therapy. Among 268 patients participating in clinical trials, one case of moderate hyperstimulation has been reported, but this cycle included concomitant use of clomiphene citrate. In contrast, menotropins (hMG) with hCG, have been variously reported to cause some degree of hyperstimulation in up to 50% of conception cycles, and severe hyperstimulation may occur in up to 1.3% of all cycles.

Several cases of allergic reactions to synthetic LHRH have been reported in the published scientific literature. Most of the reports described urticaria following administration of synthetic LHRH although one case described a serious anaphylactic reaction. In cases where it has been investigated, the allergic reactions were associated with anti-LHRH antibodies in the patient’s serum. The s.c. route of administration of synthetic LHRH would bear a greater risk of antibody induction compared to i.v. administration. In one study, the incidence of circulating antibodies in patients treated with pulsatile s.c. LHRH was found to be 3%. Some patients who develop antibodies to LHRH may become refractory to treatment.

Gonadorelin should be administered with a suitable pulsatile pump and suitable infusion catheters. The patient should be provided with detailed oral and written instructions regarding infusion pump usage and potential sepsis in order to minimize the frequency of infusion pump malfunction and inflammation, infection, mild phlebitis or hematoma at the catheter site.

Laboratory Tests: Following a diagnosis of primary hypothalamic amenorrhea, initiation of gonadorelin therapy may be monitored by the following: 1. Ovarian ultrasound – baseline, and at least weekly while the patient is on therapy or until ovulation has been documented. 2. Estradiol serum level to assess ovarian response. 3. Mid-luteal phase serum progesterone to confirm ovulation. 4. Recording of basal body temperature. 5. Clinical observation of infusion site at each visit and as needed. 6. Physical examination including pelvic at regularly scheduled visits.

Drug Interactions: None are known. Gonadorelin should not be used concomitantly with other ovulation stimulators.

Drug/Laboratory Test Interactions : None are known.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Since GnRH is a natural substance normally present in humans, long-term studies in animals have not been performed to evaluate carcinogenic potential. Mutagenicity testing was not done.

Pregnancy: Reproductive studies (teratology and embryotoxicity) performed in rats and rabbits have not revealed any evidence of harm to the fetus due to gonadorelin acetate. There was no evidence of teratogenicity when gonadorelin was administered i.v. up to 120 g/kg/day (>70 times the recommended human dose of 5 g per pulse) in rats and rabbits.

Studies in pregnant women have shown that gonadorelin does not increase the risk of abnormalities when administered during the first trimester of pregnancy. It appears that the possibility of fetal harm is remote, if the drug is used during pregnancy. In clinical studies, 47 pregnant patients have used gonadorelin during the first trimester of pregnancy (51 pregnancies) and the drug had no apparent adverse effect on the course of pregnancy. Available follow-up reports on infants born to these women revealed no adverse effects or complications that were attributable to gonadorelin. Nevertheless, because the studies in humans cannot rule out the possibility of harm, gonadorelin should be used during pregnancy only for maintenance of the corpus luteum in ovulation induction cycles.

Lactation: It is not known whether this drug is excreted in human milk. There is no indication for use of gonadorelin in a nursing woman.

Children: Not applicable.

Adverse Reactions: The majority of adverse effects are associated with the parenteral route of administration of the drug and are generally confined to superficial thrombophlebitis and injection site irritation.

Adverse reactions have been reported in approximately 10% of treatment regimens in pivotal clinical trials. Ten of 268 patients interrupted therapy because of an adverse reaction but subsequently resumed treatment. One other subject did not resume treatment.

In clinical studies involving 268 women, one case of moderate ovarian hyperstimulation has been reported. This cycle included concomitant use of clomiphene. This low incidence of hyperstimulation appears to be due to the preservation of normal feedback mechanisms of the pituitary-ovarian axis. Despite the preservation of feedback mechanisms, some incidents of multiple follicle development, multiple pregnancy and spontaneous termination of pregnancy have been reported. In clinical studies involving 142 pregnancies, delivery information was available on 89 pregnancies. Eleven of these gonadorelin-induced pregnancies (12%) were multiple (10 sets of twins, 1 set of triplets).

The following adverse reactions are related to use of an infusion pump: inflammation, infection, mild phlebitis, or hematoma at the catheter site. Additionally, infusion set malfunction and interruption of infusion may occur; this has no known adverse effect other than interruption of therapy.

Anaphylaxis (bronchospasm, tachycardia, flushing, urticaria, induration at injection site) has been reported with the related polypeptide hormone gonadorelin hydrochloride (Factrel). Antibody formation has occurred in approximately 3% of patients treated with Factrel via the s.c. route. In some cases, these appear to be related to a decreased effectiveness of the drug.

Ovarian Cancer: Ovarian cancer has been reported in a very small number of infertile women who have been treated with fertility drugs. A causal relationship between treatment with fertility drugs and ovarian cancer has not been established.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Continuous, non-pulsatile exposure to gonadorelin could temporarily reduce pituitary responsiveness. If the pump should malfunction and deliver the entire contents of the 3.2 mg system, no harmful effects would be expected. Bolus doses as high as 3 000 g of gonadorelin hydrochloride have not been harmful. Pituitary hyperstimulation and multiple follicle development can be minimized by adhering to recommended doses, and appropriate monitoring of follicle formation (see Precautions).

The LD50 values (mg/kg) in the mouse are >400, >3 000, and >4 000 when GnRH is administered i.v., s.c. and orally, respectively. The LD50 values (mg/kg) in the rat are >200, >2 000, and >3 000 when GnRH is administered i.v., s.c. and orally, respectively.

Administration of 640 g/kg in monkeys as a single i.v. bolus resulted in no compound-related effects in clinical observations or gross morphologic evaluations.

Dosage And Administration: Dosages between 1 and 20 g have been successfully used in clinical studies. The recommended dose in primary hypothalamic amenorrhea is 5 g every 90 minutes, administered either s.c. or i.v. This is delivered using the 0.8 mg solution at 50 L per pulse. Sixty-eight percent of the 5 g every 90 minutes regimens induced ovulation in patients with primary hypothalamic amenorrhea, when administered i.v.

Some women may require a reduction in the recommended dose of 5 g should laboratory testing and patient monitoring indicate an inappropriate response. While most primary hypothalamic amenorrhea patients will ovulate during the first cycle of 5 g therapy, some may be refractory to this dose. The recommended treatment interval before dose adjustment is 21 days. It may be necessary to raise the dose cautiously, and in stepwise fashion if there is no response after 3 treatment intervals. All dose changes should be carefully monitored for inappropriate response.

The response to gonadorelin usually occurs within 2 to 3 weeks after therapy initiation. When ovulation occurs, therapy should be continued for another 2 weeks to maintain the corpus luteum. Lutrepulse dose and dosing frequency should remain the same.

Administration: Gonadorelin is to be reconstituted aseptically with 8 mL of the diluent provided (isotonic sterile sodium chloride for injection). The drug product should be reconstituted immediately prior to use and transferred to a plastic reservoir. First withdraw 8 mL of the saline diluent and then inject it onto the lyophile (drug product) cake. The product is shaken for a few seconds to produce a solution which should be clear, colorless, and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or discoloration are present, the solution should not be used.

The reconstituted solution is administered either i.v. or s.c. using a suitable pulsatile pump. The pump could be set to deliver either 25 or 50 L of solution, based upon the dose selected, over a pulse period of 1 minute, and at a pulse frequency of 90 minutes. If 50 L per pulse is used with a pulse frequency of 90 minutes, the 8 mL of solution should last 7 days. If 25 L per pulse is used with a pulse frequency of 90 minutes, the 8 mL of solution should last 14 days.

Availability And Storage: Each 10 mL vial of lyophilized, sterile powder contains: gonadorelin acetate 0.8 or 3.2 mg (gonadorelin base 0.73 mg and 2.91 mg respectively) and mannitol 10 mg as a carrier. Packages of 1 vial and a 10 mL vial of sterile, isotonic sodium chloride diluent. The product is stable when stored at room temperature (15 to 30°C) in the unopened package. The reconstituted solution is stable for up to 45 days at 24 to 37°C when stored in vials and reservoir bags, and remains stable and uncontaminated for up to 16 hours in catheter tubing.

LUTREPULSE™ Ferring Gonadorelin Acetate Ovulatory Agent

Connected Diseases :

Amenhorrhea, Primary

General Illness Information Common Name: AMENHORRHEA, PRIMARY Medical Term: None specified Description: Complete absence of menstruation in a young woman who is at least 16…