Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) Busrelina
2) Buserelinum
3) Buszerelin
4) S74-6766
5) Molecular Formula: C60-H86-N16-O13
6) CAS 57982-77-1

1) Deslorelina
2) Deslorelinum
3) D-Trp LHRH-PEA
4) Molecular Formula: C64-H83-N17-O12
5) CAS 57773-65-6

1) Follitropin alfa
2) Lutropin alfa
3) Lutropin alfa/follitropin alfa

1) Follicle Stimulating Hormone-releasing Factor
2) GnRH
3) Gonadoliberin
4) Gonadorelina
5) Gonadorelinum
6) Hoe-471
7) LH/FSH-RF
8) LH-RH
9) Luteinizing Hormone-releasing Factor
10) Molecular Formula: C55-H75-N17-O13
11) CAS 33515-09-2

1) Goserelina
2) Goserelinum
3) Goszerelin
4) ICI-118630
5) Molecular Formula: C59-H84-N18-O14
6) CAS 65807-02-5 (goserelin)
7) CAS 145781-92-6 (goserelin acetate)

1) Histrelina
2) Histrelinum
3) ORF-17070
4) RWJ-17070
5) Molecular Formula: C66-H86-N18-O12
6) CAS 76712-82-8 (histrelin)
7) CAS 220810-26-4 (histrelin acetate)

1) Leuprorelin
2) Leuprorelinum
3) Molecular Formula: C59-H84-N16-O12
4) CAS 53714-56-0 (leuprolide)
5) CAS 74381-53-6 (leuprolide acetate)

1) Acetato de nafarelina
2) D-NaI(2)6-LHRH acetate hydrate
3) RS-94991298
4) Nafarelin acetate
5) Molecular Formula: C66-H83-N17-O13, x C2-H4-O2,yH2O
6) CAS 76932-56-4 (nafarelin)
7) CAS 86220-42-0 (nafarelin acetate)

1) Triptorelina
2) Triptorelinum
3) AY-25650
4) BIM-21003
5) BN-52014
6) CL-118532
7) [6-D-Tryptophan] luteinizing hormone-releasing factor
8) Molecular Formula: C64-H82-N18-O13
9) CAS 57773-63-4 (triptorelin)
10) CAS 140194-24-7 (triptorelin acetate)
11) CAS 124508-66-3 (triptorelin embonate)

1.2.1) MOLECULAR FORMULA
1) BUSERELIN: C6-O-H86-N16-O13
2) DESLORELIN: C64-H83-N17-O12
3) GONADORELIN: C55H75N17O13
4) GOSERELIN ACETATE: C59H84N18O14.C2H4O2
5) HISTRELIN: C66H86N18O12
6) LEUPROLIDE: C59-H84-N16-O12
7) NAFARELIN: C66-H83-N17-O13
8) TRIPTORELIN: C64H82N18O13

Available Forms Sources

A)

1) Goserelin is available as 3.6 mg and 10.8 mg goserelin acetate implants for subcutaneous administration (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info ZOLADEX(R) 10.8 mg implant, 2005).
2) Follitropin alfa/lutropin alfa combination product is available as a vial containing 150 international Units (equivalent to 11 mcg) of follitropin alfa and 75 IU (equivalent to 3 mcg) of lutropin alfa. After reconstitution, each mL of the solution contains 150 IU of follitropin alfa and 75 IU of lutropin alfa (Prod Info Pergoveris subcutaneous injection solution, 2012).
3) Histrelin is available as a 50 mg histrelin acetate implant for subcutaneous administration (Prod Info VANTAS(R) implant, 2005).
4) Leuprolide acetate is available as a 72 mg (65 mg leuprolide base) implant for subcutaneous administration. It is also available as 3.75 mg/vial, 7.5 mg/vial, 11.25 mg/vial, 22.5 mg/vial, and 30 mg/vial injection in a depot formulation, 7.5 mg/vial, 11.25 mg/vial, and 15 mg/vial injection in a pediatric depot formulation, and 1mg/0.2 mL , 22.5 mg/vial, 30 mg/vial, and 45 mg/vial injection for subcutaneous administration (Prod Info leuprolide acetate subcutaneous injection, 2006; Prod Info LUPRON DEPOT(R) subcutaneous injection, 2006; Prod Info LUPRON DEPOT-PED(R) injection, 2006; Prod Info Viadur(R), 2005).
5) Nafarelin acetate is available as 2 mg/mL nafarelin base in a nasal solution for administration as a spray. Each actuation of the nasal spray delivers approximately 100 microliters containing approximately 200 mcg nafarelin base (Prod Info SYNAREL(R) nasal solution, 2005a).
6) Triptorelin pamoate is available as 3.75 mg in a depot formulation for intramuscular administration and as 11.25 mg in a long-acting formulation for intramuscular administration (Prod Info TRELSTAR(R) DEPOT IM injection, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005).

B)

1) Goserelin acetate is indicated for the palliative treatment of prostate cancer and advanced breast cancer, and for the management of endometriosis (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info ZOLADEX(R) 10.8 mg implant, 2005).
2) Gonadorelin hydrochloride is indicated for evaluating the functional capacity and response of the anterior pituitary to gonadotropin releasing hormone. It is indicated for evaluating residual gonadotropic function of the pituitary following removal of a pituitary tumor by surgery and/or radiation (Prod Info FACTREL(TM) injection, 2003).
3) Histrelin acetate is indicated for palliative therapy of advanced prostate cancer (Prod Info VANTAS(R) implant, 2005).
4) Leuprolide acetate is indicated for the palliative treatment of advanced prostate cancer, for the treatment of endometriosis and anemia associated with uterine leiomyomata (fibroids), and for the treatment of central precocious puberty in children (Prod Info LUPRON DEPOT(R) subcutaneous injection, 2006; Prod Info LUPRON DEPOT-PED(R) injection, 2006; Prod Info LUPRON DEPOT(R) injection suspension, 2005; Prod Info Viadur(R), 2005).
5) Follitropin alfa/lutropin alfa combination product is indicated for the stimulation of follicular development in adult women with severe luteinizing hormone and follicle stimulating hormone deficiency (defined in clinical trials as endogenous serum luteinizing hormone less than 1.2 international units/L) (Prod Info Pergoveris subcutaneous injection solution, 2012).
6) Nafarelin nasal solution is indicated for the management of endometriosis and for the treatment of central precocious puberty in children (Prod Info SYNAREL(R) nasal solution, 2005a).
7) Triptorelin pamoate is indicated for the palliative treatment of advanced prostate cancer (Prod Info TRELSTAR(R) DEPOT IM injection, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Leuprolide acetate is indicated for the palliative treatment of advanced prostate cancer, for the treatment of endometriosis and anemia associated with uterine leiomyomata (fibroids), and for the treatment of central precocious puberty in children. Goserelin acetate is indicated for the palliative treatment of prostate cancer and advanced breast cancer, and for the management of endometriosis. Histrelin acetate and triptorelin pamoate are indicated for palliative therapy of advanced prostate cancer. Nafarelin nasal solution is indicated for the management of endometriosis and for the treatment of central precocious puberty in children. Follitropin alfa/lutropin alfa combination product is indicated for the stimulation of follicular development in adult women with severe luteinizing hormone and follicle stimulating hormone deficiency.
B) PHARMACOLOGY: Luteinizing hormone releasing hormone (LH-RH) agonists will initially stimulate the release of pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), resulting in a transient increase of gonadal steroidogenesis. However, chronic administration of the LH-RH agonists results in inhibition of gonadotropin secretion leading to suppression of ovarian and testicular steroidogenesis. Ongoing therapy with these agents results in a decrease in estrogen and testosterone levels which can lead to a variety of symptoms.
C) EPIDEMIOLOGY: Overdose is rare. Severe toxicity is not expected.
D) WITH THERAPEUTIC USE

1) Initial administration of luteinizing hormone releasing hormone (LH-RH) agonists may result in disease "flare" characterized by increased bone pain, urinary obstruction, or spinal cord compression, and may last for 1 to 2 weeks of administration. Continued therapy results in a decrease in estrogen and testosterone levels, leading to a variety of related adverse effects including flushing, acne, headaches, depression, gynecomastia, impotence, decreased libido, amenorrhea, vaginal dryness, and osteopenia. Other adverse effects, reported with LH-RH agonist therapy, include injection site reactions (ie, pain, erythema, swelling, bruising), edema, rashes, alopecia, nausea and vomiting, abdominal pain, and weight gain. RARE: Hypersensitivity reactions, anaphylaxis, and pituitary apoplexy have been rarely reported.

E) WITH POISONING/EXPOSURE

1) Overdose information is limited. It is anticipated that overdose effects would be an extension of adverse effects reported with therapeutic use.

0.2.10)

A) WITH THERAPEUTIC USE

1) Vaginal dryness, impotence, and decreased libido are common effects following therapeutic administration of LH-RH agonists and are due to a decrease in estrogen or testosterone levels. Other adverse effects that may occur with LH-RH agonist therapy include ovarian hyperstimulation syndrome, amenorrhea, urinary dysfunction, priapism, and testicular atrophy.

0.2.16)

A) WITH THERAPEUTIC USE

1) Hot flashes and gynecomastia have commonly occurred with LH-RH agonist therapy and are related to a decrease in estrogen and testosterone levels.
2) Pituitary apoplexy, galactorrhea, and thyroiditis are less frequent occurrences with therapy.

0.2.20)

A) Luteinizing hormone releasing hormone (LH-RH) agonists are classified as FDA pregnancy category X and are, therefore, contraindicated in women who are pregnant or who may become pregnant while taking the medication. Animals studies have demonstrated major fetal abnormalities, fetal mortality, and decreased fetal weights in animals exposed to LH-RH agonists during gestation. Although it is unknown whether these drugs are excreted in breast milk, leuprolide use is contraindicated for use in nursing mothers.

0.2.21)

A) GOSERELIN

1) At the time of this review, the manufacturer did not report any carcinogenic potential.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.6)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most exposures are mild and require only supportive care. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose. For patients with severe ovarian hyperstimulation syndrome, initiate intravenous hydration, monitor fluid input and output, and initiate deep venous thrombosis prophylaxis.

C) DECONTAMINATION

1) Gastrointestinal decontamination is not indicated since these medications are administered via the intramuscular or subcutaneous route or intranasally.

D) AIRWAY MANAGEMENT

1) Airway management is not likely to be an issue. Provide supportive care.

E) ANTIDOTE

1) None

F) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with unintentional exposure may be observed at home if asymptomatic.
2) OBSERVATION CRITERIA: Symptomatic patients with uncontrollable nausea, vomiting, or abdominal pain should be evaluated in a healthcare facility. Patients may be discharged if asymptomatic 6 hours after exposure.
3) ADMISSION CRITERIA: Symptomatic patients requiring ongoing supportive care may need admission. Patients with evidence of ovarian hyperstimulation syndrome may require admission.
4) CONSULT CRITERIA: Severe poisoning does not usually occur with these agents; however, if concerned about ovarian hyperstimulation syndrome, consult an obstetrician/gynecologist or specialist in reproductive medicine.

G) PITFALLS

1) Failure to consider ovarian hyperstimulation syndrome in patients utilizing luteinizing hormone releasing hormone (LH-RH) agonists. Failure to consider these agents as an etiology for elevated liver enzymes or hypertension.

H) PHARMACOKINETICS

1) BUSERELIN: Protein binding: 15%; renal excretion: SubQ, 13% to 30%; intranasal: less than 1%; elimination half-life: 72 to 80 min.
2) GOSERELIN: Protein binding: 27%; Vd: 44.1 L (men); 20.3 L (women); renal excretion: more than 90% excreted in urine with 20% as unchanged drug; elimination half-life: 4.2 hours (men); 2.3 hours (women).
3) HISTRELIN: Protein binding: 29%; Vd: 58.4 L; elimination half-life: about 4 hours.
4) LEUPROLIDE: Protein binding: 43% to 49%; Vd: 27 L; renal excretion: less than 5% of the dose was recovered as the parent drug and the major metabolite, the pentapeptide; elimination half-life: about 3 hours.
5) NAFARELIN: Protein binding: 78% to 84%; renal excretion: 44% to 55% of the dose was recovered in the urine; elimination half-life: 2.7 hours (intranasal), and 2 to 5 hours (SubQ).
6) TRIPTORELIN: Vd: 33 L; renal excretion: 41.7% was excreted as unchanged drug; elimination half-life: 30 minutes to 2.8 hours.

I) DIFFERENTIAL DIAGNOSIS

1) Ovarian hyperstimulation syndrome.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) Initial administration of luteinizing hormone releasing hormone (LH-RH) agonists may result in disease "flare" characterized by increased bone pain, urinary obstruction, or spinal cord compression, and may last for 1 to 2 weeks of administration. Continued therapy results in a decrease in estrogen and testosterone levels, leading to a variety of related adverse effects including flushing, acne, headaches, depression, gynecomastia, impotence, decreased libido, amenorrhea, vaginal dryness, and osteopenia. Other adverse effects, reported with LH-RH agonist therapy, include injection site reactions (ie, pain, erythema, swelling, bruising), edema, rashes, alopecia, nausea and vomiting, abdominal pain, and weight gain. RARE: Hypersensitivity reactions, anaphylaxis, and pituitary apoplexy have been rarely reported.

E)

1) Overdose information is limited. It is anticipated that overdose effects would be an extension of adverse effects reported with therapeutic use.

Heent

3.4.5)

A) WITH THERAPEUTIC USE

1) Intranasal administration of LH-RH agonists has resulted in mild irritation of the nasal mucosa (Prod Info SYNAREL(R) nasal solution, 2005; Brogden et al, 1990; Roila, 1989; Henzl et al, 1988; Lin et al, 1986; Gudmundsson et al, 1986; Bergquist et al, 1979).
2) EXACERBATION OF SINUSITIS: A 34-year-old woman experienced an acute exacerbation of her chronic maxillary sinusitis approximately 14 days after beginning nafarelin therapy for the treatment of endometriosis. The patient recovered following surgical intervention and cessation of nafarelin therapy (Heinig et al, 2001).

Cardiovascular

3.5.2)

A) HYPERTENSIVE DISORDER

1) WITH THERAPEUTIC USE

a) BUSERELIN: Increased blood pressure has been reported occasionally during buserelin therapy (Roila, 1989; Barrett & Dalton, 1987).
b) LEUPROLIDE: Hypertension has been reported with leuprolide acetate injection during postmarketing experience (Prod Info LUPRON DEPOT-PED 3 month intramuscular injection powder lyophilized for suspension, 2011; Prod Info LUPRON DEPOT-PED 1 month intramuscular injection powder lyophilized for suspension, 2011).

B) PHLEBITIS

1) WITH THERAPEUTIC USE

a) GONADORELIN: Mild phlebitis has been reported at the site of infusion of gonadorelin acetate (Prod Info Lutrepulse(R), 1991a).

C) PALPITATIONS

1) WITH THERAPEUTIC USE

a) TRIPTORELIN: Palpitations have been reported occasionally during triptorelin therapy (Geisthoevel et al, 1989).

Respiratory

3.6.2)

A) FIBROSIS OF LUNG

1) WITH THERAPEUTIC USE

a) BUSERELIN: Pulmonary fibrosis was described in one elderly patient with prostate cancer following 2.5 months of therapy with subcutaneous buserelin plus nilutamide (antiandrogen) (Seigneur et al, 1988). This is the first report of this complication, and further studies are required to determine the propensity of this combination to induce pulmonary reactions.
b) LEUPROLIDE: A 79-year-old man, with prostate cancer, developed nausea and vomiting, fever, sweats, dyspnea, anorexia, and malaise after receiving his first injection of leuprolide. A pulmonary exam revealed bibasilar rales and laboratory data revealed elevated white blood cell and platelet counts (18,000 mm3 and 863,000 mm3, respectively). Chest x-ray showed bibasilar pulmonary infiltrates with pleural effusions and pulmonary congestion. An open lung biopsy revealed interstitial fibrosis with cellular infiltrates, alveolar hemorrhage, and diffuse alveolar damage. Rapid improvement of the patient's condition occurred within 2 weeks after beginning corticosteroid therapy and cessation of leuprolide therapy (Crayton et al, 1991).

B) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) LEUPROLIDE

1) A case of interstitial pneumonitis induced by bicalutamide and leuprorelin acetate was reported in a 79-year-old man being treated with maximal androgen blockade for prostate cancer. After 4 weeks of bicalutamide 80 mg and 2 weeks of leuprorelin 3.75 mg treatment, the patient presented with severe dyspnea, cough and fever. Sputum and blood cultures were negative for bacteria and fungus and computed tomography was consistent with interstitial pneumonitis. The patient received steroid pulse therapy for 3 days. Symptoms resolved following steroid therapy and chest X-ray improved. Therapy with bicalutamide and leuprorelin was discontinued and the patient's prostate specific antigen level has not been detected for more than one year (Shioi et al, 2003).
2) One case of interstitial pneumonitis was reported on a 75-year-old man diagnosed with adenocarcinoma of the prostate. He was started on flutamide 375 mg daily and leuprolide acetate 3.75 mg monthly. On day eight of flutamide therapy, leuprolide acetate was injected. The patient immediately developed high fever and cough. Physical examination demonstrated fine crackles in the lower lung field, and laboratory tests showed an elevated white blood count and C-reactive protein level, and hypoxemia. Chest x-ray and computerized tomography revealed a reticulonodular pattern that was prominent at the base of the lungs. Treatment with hydrocortisone succinate, artificial respiration, and the withdrawal of flutamide was unsuccessful. The patient died of respiratory failure one month later. Autopsy confirmed interstitial pneumonitis. There were several reports linking leuprolide to interstitial pneumonitis. Unlike nilutamide, flutamide had not been reported to cause interstitial pneumonitis (Azuma et al, 1999).

Neurologic

3.7.2)

A) HEADACHE

1) WITH THERAPEUTIC USE

a) Transient headaches have been reported frequently with LH-RH agonist therapy (Prod Info Pergoveris subcutaneous injection solution, 2012; Prod Info LUPRON DEPOT-PED 3 month intramuscular injection powder lyophilized for suspension, 2011; Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info VANTAS(R) implant, 2005; Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005; Prod Info SYNAREL(R) nasal solution, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005; Brogden et al, 1990; Steingold et al, 1987).

B) SPINAL CORD COMPRESSION

1) WITH THERAPEUTIC USE

a) Signs of spinal cord compression (eg, leg weakness, sphincter dysfunction, sudden paraplegia requiring laminectomy) have been described rarely in association with disease flare in prostatic cancer patients during initiation of LH-RH agonist therapy (Prod Info LUPRON DEPOT(R) subcutaneous injection, 2006; Prod Info VANTAS(R) implant, 2005; Roila, 1989; Waxman et al, 1985)
b) GOSERELIN: Epidural spinal cord compression developed within 1 week of initiation of goserelin therapy in 2 prostatic cancer patients with extensive bone metastases. Spontaneous progression of the disease could not be ruled out, however, it is possible that the goserelin-induced rise in testosterone, resulting in tumor flares, may have been responsible for this complication (Ahmann et al, 1987).

C) ANXIETY

1) WITH THERAPEUTIC USE

a) HISTRELIN: Anxiety, depression, and irritability may occur in patients receiving subcutaneous histrelin 100 micrograms/day or 4 mcg/kg/day; these symptoms may be severe enough to necessitate discontinuation of therapy (Coddington et al, 1986; Steingold et al, 1987).

D) FATIGUE

1) WITH THERAPEUTIC USE

a) HISTRELIN: Fatigue was reported in 9.9% of patients with prostate cancer during clinical trials of histrelin implants (Prod Info VANTAS(R) implant, 2005).

E) LETHARGY

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: In an open-label, multicenter study of prostate cancer patients, lethargy or fatigue was reported in 13.2% of patients treated with leuprolide acetate depot 45 mg every 6 months for 48 weeks (n=151) of which 11.9% were considered to be treatment related (Prod Info LUPRON DEPOT(R) intramuscular suspension for depot injection, 2011).

F) DIZZINESS

1) WITH THERAPEUTIC USE

a) Dizziness was reported in 11% of women treated monthly with leuprolide acetate depot 3.75 mg for 6 months (n=166), 3% of women treated with danazol 800 mg/day (n=136), and 0% of women treated with placebo (n=31) in 2 controlled clinical studies of women with endometriosis (Prod Info Lupron Depot(R) IM injection, powder, lyophilized, for suspension, 2008; Prod Info Lupron Depot(R) IM Injection, powder, lyophilized, for suspension, 2008).

G) DEPRESSIVE DISORDER

1) WITH THERAPEUTIC USE

a) Depression, associated with a decrease in testosterone or estrogen levels, has occurred with LH-RH agonist therapy (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005; Prod Info SYNAREL(R) nasal solution, 2005). In one instance, testosterone administration appeared to reverse the symptoms of leuprolide-induced depression in a 70-year-old man (Freeman & Freeman, 2003).

H) PARESTHESIA

1) WITH THERAPEUTIC USE

a) CASE REPORT/NAFARELIN: A 26-year-old woman was prescribed nafarelin spray to treat her dysmenorrhea. Twenty-three days after beginning nafarelin therapy, the patient experienced neck and facial paresthesia contralateral to drug administration, approximately 15 minutes after inhalation, and persisting for several hours. Nafarelin was discontinued and the paresthesia did not recur (Penzias et al, 1991).

I) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT/LEUPROLIDE: A 13-year-old adolescent, with a prior history of medulloblastoma, treated with chemotherapy and radiation, along with short stature syndrome and moderate mental retardation, experienced several atypical absence seizures (approximately 10 times daily) 3 months after beginning therapy with a long-acting formulation of leuprolide acetate. There was no evidence of tumor recurrence. The patient received ethosuximide and the seizures disappeared two weeks later. The next dose of leuprolide was given with ethosuximide and, 1 hour later, the seizures recurred. The seizures again disappeared 1 month later, following cessation of leuprolide therapy and administration of anticonvulsants. Two years and 6 months later, the seizures recurred without leuprolide therapy. Administration of anticonvulsants resulted in resolution of the seizures 2 months later (Akaboshi & Takeshita, 2000). The authors suggested that the seizures associated with LA administration were may have been due in part to the underlying brain damage in this patient.

J) EXTRAPYRAMIDAL MOVEMENTS

1) WITH THERAPEUTIC USE

a) CASE REPORT/LEUPROLIDE: Extrapyramidal symptoms (akathisia-like movement, a stereotyped circular rotation of the trunk) developed in a 54-year-old man after 10 months of leuprolide acetate depot injections of 3.75 mg every 4 weeks for prostate cancer. Concomitant medications included paroxetine 40 mg/day, lorazepam 0.5 mg twice daily, and zolpidem 10 mg daily for major depressive disorder and anxiety. A thorough physical and neurologic examination, including a CT scan of the brain, showed no abnormalities. The akathisia-like movement persisted after paroxetine was discontinued and replaced with duloxetine but completely stopped when leuprolide therapy was interrupted. Upon resuming regular injections of leuprolide 5 weeks later, the akathisia-like movement recurred. Propranolol 20 mg three times daily was administered resulting in significantly decreased frequency and intensity of the movement (Kuo et al, 2014).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting have been reported following therapeutic administration of LH-RH agonists (Prod Info Pergoveris subcutaneous injection solution, 2012; Prod Info Lupron Depot(R) IM injection, powder, lyophilized, for suspension, 2008; Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005; Prod Info TRELSTAR(R) DEPOT IM injection, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005; Brogden et al, 1990).
b) GOSERELIN: Nausea has been reported with prolonged goserelin therapy (6 months) in patients with breast cancer (Williams et al, 1986).

B) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal pain have been reported following therapeutic administration of LH-RH agonists (Prod Info Pergoveris subcutaneous injection solution, 2012; Prod Info Lupron Depot(R) IM injection, powder, lyophilized, for suspension, 2008; Prod Info Factrel(R), 1991).
b) BUSERELIN: Abdominal pain was reported in 7% of women treated with buserelin for endometriosis or uterine leiomyoma (Brogden et al, 1990).
c) GONADORELIN: Abdominal discomfort has been reported, rarely, with gonadorelin hydrochloride (Prod Info Factrel(R), 1991).

C) CONSTIPATION

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: In an open-label, multicenter study of prostate cancer patients, constipation was reported in 9.9% of patients treated with leuprolide acetate depot 45 mg every 6 months for 48 weeks (n=151) of which 3.3% were considered to be treatment related (Prod Info LUPRON DEPOT(R) intramuscular suspension for depot injection, 2011).
b) HISTRELIN: Constipation was reported in 3.5% of patients (n=171) with prostate cancer during clinical trials of histrelin implants (Prod Info VANTAS(R) implant, 2005).

Hepatic

3.9.2)

A) INCREASED LIVER ENZYMES

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: Post-treatment aminotransferase concentrations were elevated to at least twice the baseline value and above the upper limit of the normal range in 3% of patients with uterine fibroids treated with Lupron Depot(R) 3.75 mg (Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005).

Genitourinary

3.10.1)

A) WITH THERAPEUTIC USE

1) Vaginal dryness, impotence, and decreased libido are common effects following therapeutic administration of LH-RH agonists and are due to a decrease in estrogen or testosterone levels. Other adverse effects that may occur with LH-RH agonist therapy include ovarian hyperstimulation syndrome, amenorrhea, urinary dysfunction, priapism, and testicular atrophy.

3.10.2)

A) UROGENITAL FINDING

1) WITH THERAPEUTIC USE

a) BUSERELIN

1) Vaginal dryness, breakthrough bleeding, and decreased libido are frequent adverse effects of buserelin in women. Vaginal dryness has been reported in up to 28% of patients with endometriosis or uterine leiomyoma during buserelin therapy, with reduced libido occurring in up to 12% (Brogden et al, 1990; Lemay, 1989).
2) With intermittent buserelin combined with a progestin, normal or withdrawal menstrual bleeding has occurred in 81% to 100% of women; however, breakthrough bleeding has been a complication in 14% to 28% (Lemay et al, 1985; Brogden et al, 1990).
3) Premenstrual syndrome-like symptoms have been reported in up to 13% of women treated with buserelin for endometriosis (Brogden et al, 1990). Worsening of symptoms has also occurred in women treated for premenstrual syndrome with buserelin (Bancroft et al, 1987; Brogden et al, 1990).

b) LEUPROLIDE

1) Vaginitis was reported in 28% of patients receiving Lupron Depot(R) 3.75 mg for endometriosis (Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005).

c) NAFARELIN

1) Vaginal dryness and dyspareunia have been reported with nafarelin therapy (Prod Info SYNAREL(R) nasal solution, 2005; Brenner et al, 1985; Schriock et al, 1985).

B) IMPOTENCE

1) WITH THERAPEUTIC USE

a) BUSERELIN: Impotence has been reported in up to 100% of prostatic cancer patients during buserelin therapy (Presant et al, 1987; Roila, 1989; Brogden et al, 1990).
b) DESLORELIN: Impotence and decreased libido have been reported during deslorelin therapy (50 mcg daily) in males (Linde et al, 1981a; Johnson et al, 1985). Concurrent administration of testosterone enanthate (100 mg intramuscularly once weekly) has been effective in preserving potency and libido while enabling the desired effect of reversible oligozoospermia in male patients (Doelle et al, 1983).
c) NAFARELIN: Impotence occurred in 100% of 9 men treated for 6 months with nafarelin 400 mcg/day subcutaneously for benign prostatic hyperplasia. Decreased libido is also a common adverse effect of prolonged nafarelin therapy (Peters & Walsh, 1987; Henzl et al, 1988). Increased libido has been rarely reported (Brenner et al, 1985).

C) PRIAPISM

1) WITH THERAPEUTIC USE

a) GONADORELIN: Priapism has been reported (Whalen et al, 1991).

D) ATROPHY OF TESTIS

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: Testicular atrophy was reported following subcutaneous administration of leuprolide in patients with prostate cancer (Prod Info ELIGARD(R) 30 mg subcutaneous injection, 2006; Prod Info LUPRON DEPOT(R) subcutaneous injection, 2006). Testicular atrophy and pain were documented in 3.8% of patients who received leuprolide acetate implants for prostate cancer (Prod Info VIADUR(R) subcutaneous implant, 2005).

E) HYPERSTIMULATION OF OVARIES

1) WITH THERAPEUTIC USE

a) Ovarian hyperstimulation syndrome (OHS), characterized by sudden ovarian enlargement, ascites with or without pain, and/or pleural effusion, has been reported with LH-RH agonist therapy. Resolution of OHS occurred following cessation of therapy (Prod Info Pergoveris subcutaneous injection solution, 2012; Brett et al, 2001; Weissman et al, 1998; Jirecek et al, 1998; Prod Info Lutrepulse(R), 1991a).
b) Triptorelin administration for ovarian stimulation resulted in ovarian hyperstimulation syndrome (OHS) in a 37-year-old woman with polycystic ovary syndrome. After several failed ovarian stimulation attempts with clomiphene citrate and follicle stimulating hormone (FSH), triptorelin 3.75 milligrams (mg) was given, followed by FSH. Absence of ovarian activation led to doubling of the FSH dose for 4 days. The patient developed mild OHS, which resolved spontaneously. Three months later, triptorelin 3.75 mg alone was given. Estradiol levels became highly elevated and the ovaries greatly enlarged. The patient developed nausea, vomiting, and abdominal discomfort. The symptoms subsided over the following 7 days (Campo et al, 2000).

F) AMENORRHEA

1) WITH THERAPEUTIC USE

a) BUSERELIN: During continuous buserelin administration for female contraception, amenorrhea has been reported in 22% to 35% of cycles and oligomenorrhea in 38% to 78%; regular menstrual-like bleeding has been observed in 0% to 37% of cycles (Brogden et al, 1990; Schmidt-Gollwitzer et al, 1981; Anon, 1987).
b) NAFARELIN: All female patients treated with intranasal nafarelin 500 mcg twice daily or nafarelin acetate 500 mcg twice daily for 6 months have experienced amenorrhea and anovulation (Andreyko et al, 1986; Schriock et al, 1985). Ovulatory menses generally returns within 30 to 50 days of nafarelin discontinuation (Schriock et al, 1985; Brenner et al, 1985).

G) INCREASED FREQUENCY OF URINATION

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: Nocturia and increased urinary frequency were documented in 3.8% of patients treated with leuprolide acetate implants for prostate cancer (Prod Info VIADUR(R) subcutaneous implant, 2005).

Hematologic

3.13.2)

A) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) LEUPROLIDE

1) A 67-year-old man developed pure red cell aplasia after being treated with leuprolide 3.75 mg monthly for 3.5 months for prostate cancer (Maeda et al, 1998). He presented with a decreased hemoglobin and hematocrit but normal platelet and white blood cell counts. Bone marrow aspirate showed the absence of reticulocytes and the presence of severe erythroid hypoplasia. Leuprolide was discontinued and the patient improved with prednisone therapy.

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: A case of leukopenia occurred in a 46-year-old woman following four months of therapy with leuprolide acetate for uterine leiomyomata. Before initiation of therapy the patient had a leukocyte count of 6.1 with normal differential. After four months of receiving leuprolide (depot formulation) 3.75 mg IM monthly, her leukocyte count declined to 3.4; all other lab values were normal. Following discontinuation of the drug, her leukocyte count returned to normal. The patient received no other medications during this period (Grau et al, 1994).
b) NAFARELIN: One of 8 patients (12.5%) treated with intranasal nafarelin 500 mcg twice daily for endometriosis developed leukopenia with a nadir of 2500 white blood cells and 55% polymorphonuclear leukocytes after 2 months of therapy. After treatment was discontinued, WBC counts returned to the lower limit of normal; however, the cause of her leukopenia could not be determined (Schriock et al, 1985).

C) DECREASED HEMOGLOBIN

1) WITH THERAPEUTIC USE

a) NAFARELIN: A decrease in hemoglobin concentration was noted in 17 of 24 patients (71%) women using intranasal nafarelin acetate 125 or 250 mcg/day as a contraceptive for 6 months. Seven patients had a fall in hemoglobin from 1 to 1.9 gm% and 4 patients had a decrease between 2 and 2.5 gm%. White blood cell count was decreased to below 4800 in 6 subjects (25%), 3 at each dosage. There was not a significant difference between the 2 dosage groups in terms of effect on hemoglobin or WBC count (Brenner et al, 1985).

D) ANEMIA

1) WITH THERAPEUTIC USE

a) In an open-label, multicenter study of prostate cancer patients, anemia was reported in 6.6% of patients treated with leuprolide acetate depot 45 mg every 6 months for 48 weeks (n=151) of which 1.3% were considered to be treatment related (Prod Info LUPRON DEPOT(R) intramuscular suspension for depot injection, 2011).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) BUSERELIN

1) A 48-year-old woman being treated with buserelin nasal spray (900 micrograms per day) for fibroids developed roseola-like erythematous macules and spotted dark brown areas of pigmentation, 0.5 to 1 centimeter in diameter, on her trunk and extremities 3 weeks after beginning treatment. Discontinuation of buserelin treatment appeared to stop the cutaneous lesions. Treatment was restarted and new skin eruptions occurred 2 weeks later. Patch and scratch-patch testing showed no allergic reaction. Within 2 weeks of discontinuation of buserelin treatment, the erythematous macules changed to pigmented spots, which then gradually disappeared. However, some spots persisted at 2 years. The authors suggested that hormonal changes caused by buserelin may have been responsible for the cutaneous lesions (Kono et al, 2000).
2) SKIN RASHES have occurred in up to 3% of buserelin-treated prostate cancer patients (Roila, 1989; Brogden et al, 1990).

b) GOSERELIN

1) A mild, pruritic maculopapular rash caused the discontinuation of goserelin therapy in one patient (Debruyne et al, 1988). Skin reactions described as rash or urticaria occurred in 10% of 51 prostate cancer patients treated with goserelin (Kaisary et al, 1991).
2) A 75-year-old male had relapsing polychondritis associated with his monthly goserelin injections (Labarthe et al, 1997). Extensive erythemato-edematous plaques and secondary purpura occurred 3 days after starting each goserelin injection and lasted for 1 to 2 weeks.

c) LEUPROLIDE

1) CASE REPORT: A 68-year-old man, with prostate cancer, developed pruritus and erythematous papules and vesicles on his knees, elbows, and left thumb within 3 weeks of initiating leuprolide therapy (one intramuscular injection every 3 months). The symptoms would decrease in severity toward the end of each 3-month cycle, and then would flare within 1 to 3 days following the next injection. Hematoxylin and eosin staining, as well as immunofluorescence assays of the lesions and perilesional tissue, indicated the presence of dermatitis herpetiformis (DH). Following topical application of emollients, the patient's skin lesions improved; however, symptoms continued to persist and direct immunofluorescence continued to show the presence of DH (Grimwood & Guevara, 2005).

B) ACNE

1) WITH THERAPEUTIC USE

a) Acne has been reported with LH-RH agonist therapy and appears to be due to hypoestrogenism (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005; Prod Info SYNAREL(R) nasal solution, 2005; Brogden et al, 1990).

C) EXCESSIVE SWEATING

1) WITH THERAPEUTIC USE

a) BUSERELIN: Sweating is a relatively frequent adverse effect of buserelin therapy, occurring in up to 6% of women with endometriosis during intranasal administration (Brogden et al, 1990).

D) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) Injection site reactions, including pain, erythema, swelling, and bruising, have been commonly reported following subcutaneous, intramuscular, and intravenous administration of LH-RH agonists (Prod Info Pergoveris subcutaneous injection solution, 2012; Prod Info LUPRON DEPOT(R) subcutaneous injection, 2006; Prod Info VANTAS(R) implant, 2005; Hummelink et al, 1992; Prod Info Lutrepulse(R), 1991a; Brogden et al, 1990; Roila, 1989; Parmar et al, 1985; Johnson et al, 1985; Mansfield et al, 1983).

E) CELLULITIS

1) WITH THERAPEUTIC USE

a) DESLORELIN: Cellulitis has been reported rarely with subcutaneous deslorelin (Boepple et al, 1986).

F) ALOPECIA

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: Alopecia was infrequently reported with leuprolide therapy (Prod Info ELIGARD(R) 30 mg subcutaneous injection, 2006; Prod Info VIADUR(R) subcutaneous implant, 2005).
b) TRIPTORELIN: Treatment of precocious puberty with depot long-acting triptorelin (Decapeptyl(R)) resulted in androgenetic alopecia in 5 of 22 children (Kauschansky et al, 1997).

G) EDEMA

1) WITH THERAPEUTIC USE

a) LEUPROLIDE

1) In clinical trials, 3.1% of patients treated with leuprolide acetate implants experienced peripheral edema (Prod Info VIADUR(R) subcutaneous implant, 2005).
2) Edema was seen in 20.8% of orchiectomized, prostate cancer patients treated with the Lupron Depot(R)-4 Month 30 mg formulation (Prod Info LUPRON DEPOT(R) IM injection, powder, lyophilized, for suspension, 2010).

Musculoskeletal

3.15.2)

A) OSTEOPENIA

1) WITH THERAPEUTIC USE

a) A loss of bone mineral density has been reported during LH-RH agonist therapy for treatment of endometriosis and uterine fibroids, and is associated with estrogen deficiency. Bone loss may or may not be reversible upon discontinuation of the medication (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005; Prod Info SYNAREL(R) nasal solution, 2005; Choktanasiri et al, 1996; Devogelaer et al, 1993; Brogden et al, 1990; Lemay, 1989). Hormone replacement therapy may be effective in preventing or reducing the amount of bone mineral loss (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Fogelman et al, 1994).
b) TRIPTORELIN: Calcium supplementation for girls taking triptorelin for precocious puberty prevented bone demineralization. Forty girls with precocious puberty (age range 4.7 to 7.5 years) who were being treated with the long-acting GnRH analog triptorelin 3.75 milligrams intramuscularly every 28 days were randomly assigned to receive no calcium supplementation, no calcium for the first 12 months and calcium 1 gram/day for the second 12 months, or calcium 1 gram/day throughout the 2-year study. Triptorelin completely arrested pubertal development. In the unsupplemented group, volumetric bone mineral density (BMDv) (expressed in milligrams per cubic centimeter) decreased. For those who received calcium in the second year, the initial year's decrease was reversed in the second year. The group supplemented during both years showed an increase in absolute BMDv that was statistically significant at 24 months (p=0.036). The higher peak bone mass attained with calcium supplementation during development presumably will reduce the risk of osteoporosis and fractures in later years (Antoniazzi et al, 1999).

B) BONE PAIN

1) WITH THERAPEUTIC USE

a) GOSERELIN: A transient increase in bone pain during the first week of therapy has been reported in 2% to 17% of patients treated with goserelin for prostatic cancer (Debruyne et al, 1988; Ahmann et al, 1987). This may be due to an initial transient increase in serum testosterone (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005).

C) MUSCLE PAIN

1) WITH THERAPEUTIC USE

a) LEUPROLIDE: In an open-label, multicenter study of prostate cancer patients, myalgia and musculoskeletal pain was reported in 7.9% of patients treated with leuprolide acetate depot 45 mg every 6 months for 48 weeks (n=151) of which 2% were considered to be treatment related (Prod Info LUPRON DEPOT(R) intramuscular suspension for depot injection, 2011).

D) JOINT PAIN

1) WITH THERAPEUTIC USE

a) HISTRELIN: Joint stiffness and discomfort were reported in 4 of 16 patients receiving histrelin 100 mcg/day for endometriosis; symptoms resolved promptly upon discontinuation of therapy. It has been speculated that this effect may be due to an increase in urinary calcium excretion secondary to hypoestrogenism (Steingold et al, 1987).
b) LEUPROLIDE: In an open-label, multicenter study of prostate cancer patients, arthralgia was reported in 9.3% of patients treated with leuprolide acetate depot 45 mg every 6 months for 48 weeks (n=151) of which 1.3% were considered to be treatment related (Prod Info LUPRON DEPOT(R) intramuscular suspension for depot injection, 2011).

E) MUSCLE WEAKNESS

1) WITH THERAPEUTIC USE

a) LEUPROLIDE

1) CASE REPORT: An 87-year-old man, with a prior medical history of prostate cancer, presented with increasing generalized muscle weakness. Further review of his medical history indicated that he had been taking leuprolide for approximately a year since his diagnosis of prostate cancer. Laboratory data, including serum creatine kinase concentrations, were within normal limits. Manual motor testing revealed that he had moderate to severe symmetric proximal limb and neck flexor weakness and electromyography of left limb and paraspinal muscles indicated moderately severe, proximal myopathy, although there was no evidence of fiber necrosis. Cessation of leuprolide therapy resulted in a gradual improvement in walking. Six months after discontinuing the leuprolide, he was able to resume normal daily walking activities (VanGerpen & McKinley, 2002).

F) MYOSITIS

1) WITH THERAPEUTIC USE

a) LEUPROLIDE

1) CASE REPORT: A 79-year-old man, with prostate cancer, developed nausea and vomiting, edema, shoulder pain, fever, sweats, dyspnea, anorexia, malaise, myalgias, and diffuse weakness after receiving his first injection of leuprolide. Progressive muscle weakness, resulting in an inability to walk , occurred following a second injection. Laboratory data revealed serum creatine kinase (CK) level of 2728 units/L and a muscle biopsy showed muscle necrosis with degeneration and regeneration of muscle fibers indicative of polymyositis. With supportive care and cessation of leuprolide therapy, the patient recovered with a normalization of his serum CK level (Crayton et al, 1991).

Endocrine

3.16.1)

A) WITH THERAPEUTIC USE

1) Hot flashes and gynecomastia have commonly occurred with LH-RH agonist therapy and are related to a decrease in estrogen and testosterone levels.
2) Pituitary apoplexy, galactorrhea, and thyroiditis are less frequent occurrences with therapy.

3.16.2)

A) FLUSHING

1) WITH THERAPEUTIC USE

a) Hot flashes frequently occur with LH-RH agonist therapy (Prod Info LUPRON DEPOT(R) intramuscular suspension for depot injection, 2011; Prod Info TRELSTAR(R) DEPOT IM injection, 2005; Prod Info SYNAREL(R) nasal solution, 2005a; Prod Info Viadur(R), 2005; Prod Info Vantas(TM), 2004)
b) Clonidine was reported to be of benefit in treating vasomotor flushing in a small pilot study involving four male patients receiving leuprolide or goserelin for prostate cancer (Bressler et al, 1993). Clonidine was given orally or transdermally (0.1 to 0.2 milligrams daily), and titrated according to response/adverse effects.

B) GYNECOMASTIA

1) WITH THERAPEUTIC USE

a) Gynecomastia and breast tenderness have been commonly reported following therapeutic administration of LH-RH agonists (Prod Info ELIGARD(R) suspension for subcutaneous injection, 2007; Prod Info LUPRON DEPOT(R) 4 month injection suspension, 2005; Prod Info VANTAS(R) implant, 2005; Anderson et al, 1990; Debruyne et al, 1988).

C) PITUITARY APOPLEXY

1) WITH THERAPEUTIC USE

a) Rare cases of pituitary apoplexy have been reported during the postmarketing use of gonadotropin-releasing hormone (luteinizing hormone releasing hormone) agonists. A pituitary adenoma was diagnosed in most of these instances; and most cases occurred within two weeks of the initial dose, with some occurring in the first hour. In reported cases, pituitary apoplexy has manifested as sudden headache, visual changes, vomiting, altered mental status, ophthalmoplegia, and occasionally cardiovascular collapse, sometimes requiring immediate medical attention (Prod Info Viadur(R), 2005; Prod Info SYNAREL(R) nasal solution, 2005a).

D) GALACTORRHEA NOT ASSOCIATED WITH CHILDBIRTH

1) WITH THERAPEUTIC USE

a) NAFARELIN: Galactorrhea has been reported in 2 subjects receiving 125 mcg of intranasal nafarelin acetate for contraception. The first subject, a 24-year-old nulligravida woman, developed galactorrhea after 73 days of treatment. Her serum prolactin was 72.5 ng/mL. Galactorrhea developed 15 days after treatment in the second subject, a 23-year-old nulligravida woman. Serum prolactin levels during and after treatment were normal in this patient. In both patients, galactorrhea persisted after the treatment was discontinued (Brenner et al, 1985).

E) THYROIDITIS

1) WITH THERAPEUTIC USE

a) LEUPROLIDE

1) CASE REPORT (CHILD): Autoimmune thyroiditis occurred in a 9-year-old child approximately 8 months after beginning leuprolide therapy to treat central precocious puberty. The child had a decreased energy level and her thyroid gland size appeared to be at the upper limit of normal. Laboratory data revealed a low T4 level (<1.05 mcg/dL; normal range 5.6 to 11.7 mcg/dL) and an elevated TSH level (233.3 microunits/mL; normal range 0.37 to 4.5 microunits/mL). Treatment with levothyroxine along with continued leuprolide therapy resulted in a normalization of her laboratory values and clinical improvement in her energy level (Eyal & Rose, 2004).
2) CASE REPORT (ADULT): A 45-year-old woman experienced increased sweating, fatigue, increased appetite, and weight loss two weeks after receiving her fifth injection of leuprolide acetate for the treatment of uterine leiomyoma. Laboratory analysis revealed elevated T3 and T4 levels (12 picomol/L {normal 3.7 to 6.6 picomol/L} and 32 picomol/L {normal 11 to 23 picomol/L}, respectively) and suppression of her TSH level (<0.01 microunits/mL; normal 0.6 to 4.9 microunits/mL). The patient's symptoms disappeared spontaneously two weeks after onset. Two months later, the patient's T3 and T4 levels decreased below the normal range (2.9 picomol/L and 6.4 picomol/L, respectively) and her TSH level was elevated (83.6 microunits/mL). Five months after onset, her thyroid function returned to normal without requiring treatment (Kasayama et al, 2000). The authors speculate that the patient had developed silent thyroiditis triggered by leuprolide-induced hypoestrogenism.

Immunologic

3.19.2)

A) HYPERSENSITIVITY REACTION

1) WITH THERAPEUTIC USE

a) BUSERELIN: An allergic reaction to intranasal buserelin, characterized by rhinitis and asthmatic symptoms, has been described in one patient following 2 weeks of treatment for endometriosis (Crijns et al, 1991). The patient tested positive for buserelin but not benzyl alcohol (preservative).
b) GONADORELIN: Allergic reactions to gonadorelin hydrochloride that are mediated by immunoglobulin E antibody have been reported (Foster et al, 1989). A 26-year-old woman had a reaction that was characterized by a wheal and flare at the site of injection and was confirmed by subsequent skin testing. It was theorized that some patients with Kallmann's syndrome have no exposure to endogenous luteinizing hormone-releasing hormone, therefore they react to gonadorelin as a foreign protein. Another possible explanation is that a subclinical chronic inflammatory reaction at the tip of the indwelling needle may potentiate the allergenicity of gonadorelin.

B) ANAPHYLAXIS

1) WITH THERAPEUTIC USE

a) GONADORELIN: Anaphylactic reaction was described in a 28-year-old woman during the fourth course of gonadorelin hydrochloride administration for infertility (MacLeod et al, 1987). The patient received gonadorelin by intermittent intravenous infusion (0.5 mcg every 90 minutes to a total of 120 mcg) on three occasions over a period of 13 months without adverse effects. The fourth course was given over 1 year later (approximately 14 months following the 3rd course), and the patient developed facial flushing with general extension over the entire body and associated pruritus within 10 seconds following intravenous injection of less than 50 mcg gonadorelin; subsequently, a metallic taste occurred, as well as nausea, vomiting, and loss of consciousness (blood pressure, 70 mmHg systolic; pulse, 120 BPM). The patient was treated successfully with diphenhydramine and normal saline, and symptoms resolved in 24 hours. Positive skin testing confirmed the rash to be IgE-mediated.
b) Anaphylaxis has been rarely reported with leuprolide and triptorelin therapy (Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005).
c) GOSERELIN

1) CASE REPORT (CHILD): An 8-year-old child with idiopathic central precocious puberty had been receiving long-term goserelin therapy (10.8 mg subcutaneously as an implant every 2 months for 3 years), suddenly developed hives in a wheal and flare pattern, polyarthralgia, facial swelling, dysphagia, and dyspnea with acute stridor 5 days after her last injection. The patient initially recovered after removal of the goserelin implant and treatment with epinephrine, diphenhydramine, and corticosteroids; however, over the next 4 days, she experienced 8 episodes of recurrent anaphylaxis. Symptoms resolved each time with administration of epinephrine, IV hydrocortisone, and diphenhydramine every 6 hours. After careful observation of the patient over the next several days, no further episodes of anaphylaxis occurred (Lam et al, 2006). Review of the patient's medical history, prior to beginning goserelin therapy, indicated that an allergic reaction had occurred 6 months after beginning monthly intramuscular injections of leuprolide acetate. At that time, the patient responded well to administration of antihistamines and oral prednisone.
2) CASE REPORT (ADULT): A 36-year-old woman experienced a mild hypersensitivity reaction (localized pruritus, erythema, and swelling) after receiving her third goserelin injection as part of a clinical trial. Despite the reaction, she continued to receive injections. Approximately 8 hours after receiving her sixth injection, she developed pruritus and erythema at the injection site that gradually spread to her trunk and extremities, as well as swelling in her face, hands, and feet, throat tightness, and mild dyspnea. She recovered following administration of epinephrine, antihistamines, and corticosteroids (Raj et al, 1996).

Reproductive

3.20.1)

A) Luteinizing hormone releasing hormone (LH-RH) agonists are classified as FDA pregnancy category X and are, therefore, contraindicated in women who are pregnant or who may become pregnant while taking the medication. Animals studies have demonstrated major fetal abnormalities, fetal mortality, and decreased fetal weights in animals exposed to LH-RH agonists during gestation. Although it is unknown whether these drugs are excreted in breast milk, leuprolide use is contraindicated for use in nursing mothers.

3.20.2)

A) ANIMAL STUDIES

1) LEUPROLIDE: There were dose-related increases in the incidence of major fetal abnormalities when rabbits were given leuprolide on day 6 of pregnancy at test doses of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose). In rat studies, there was not an increase in major fetal abnormalities when leuprolide was given throughout gestation. At the 2 higher doses in rabbits and the highest dose in rats, the incidence of fetal mortality was increased and fetal weights were decreased. The changes in hormonal levels caused by leuprolide are expected to result in fetal mortality (Prod Info LUPRON(R) subcutaneous injection, 2009; Prod Info Lupron Depot-Ped IM injection, 2009; Prod Info Lupron Depot(R) IM injection, powder, lyophilized, for suspension, 2008; Prod Info Lupron Depot(R) IM Injection, powder, lyophilized, for suspension, 2008; Prod Info LUPRON(R) DEPOT 3 Month formulation injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) DEPOT 4 Month Formulation injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) DEPOT injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) injection, 2008; Prod Info LUPRON DEPOT(R) 7.5 mg intramuscular injection, 2011).
2) NAFARELIN: Animal studies revealed major fetal abnormalities when nafarelin was administered to rats in doses that approximated 0.5, 2, and 7 times the maximum recommended human intranasal dose. However, a similar, repeat study with administration of nafarelin during organogenesis at the same doses in rats and at doses up to 600 mcg/kg/day and 0.18 mcg/kg/day in mice and rabbits, respectively, did not result in increased fetal abnormalities. A dose-related increase in fetal mortality and decreased fetal weight, at the highest dose, have been observed in rats and rabbits (Prod Info SYNAREL(R) nasal solution, 2005).

3.20.3)

A) FDA PREGNANCY CATEGORY

1) The manufacturers have classified luteinizing hormone releasing hormone (LH-RH) agonists (goserelin, histrelin, leuprolide, leuprolide acetate and norethindrone acetate combination kit, nafarelin, and triptorelin) as FDA pregnancy category X (Prod Info LUPRON DEPOT(R) 7.5 mg intramuscular injection, 2011; Prod Info LUPRON(R) DEPOT 3 Month formulation injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) DEPOT 4 Month Formulation injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) DEPOT injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) injection, 2008; Prod Info ELIGARD(R) suspension for subcutaneous injection, 2007; Prod Info VIADUR(R) subcutaneous implant, 2005; Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info VANTAS(R) implant, 2005; Prod Info SYNAREL(R) nasal solution, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005; Prod Info LUPANETA PACK intramuscular injection powder, oral tablets, 2012; Prod Info LUPANETA PACK intramuscular injection powder, oral tablets, 2012a).

B) SPONTANEOUS ABORTION

1) Of 5 pregnancies which involved unrecognized exposure to a gonadotrophin-releasing hormone agonist during the first trimester, 3 resulted in normal, healthy term pregnancies. A missed abortion occurred in one of the remaining cases, and trisomy 18 necessitated an induced abortion in the other (Young et al, 1993).
2) GOSERELIN: A multiple pregnancy leading to miscarriage occurred in a 24-year-old woman with minimal endometriosis treated with goserelin. At the time of administration of the first 2.6-mg injection, the patient was not sure of her last period; 2 additional injections were given at 28-day intervals. Nausea, vomiting, abdominal pain and distention were reported after the third injection. The uterus was noted to be enlarged and ultrasound revealed multiple (not defined) gestational sacs. The patient miscarried at 20 weeks despite preventive measures (Pickersgill et al, 1994).

C) LACK OF EFFECT

1) In 5 cases of inadvertent exposure to gonadotrophin-releasing hormone (GnRH) analogues during early pregnancy, 4 of the females were exposed to a superpotent, long-acting gonadotrophin releasing hormone agonist, D-TRP6 LHRH, for pituitary suppression as part of an in vitro fertilization-embryo transfer (IVF-ET) program. Because of the long-acting nature of this agent, the subsequently diagnosed pregnancies were certainly subjected to the effects of the drug during the period of organogenesis. Five normal children were born to 4 of the women, who all elected to continue their pregnancies once the diagnosis was made, despite the lack of data regarding the outcome of pregnancies exposed to GnRH agonists in the early stages. One patient suffered a complete spontaneous abortion 38 days after her last menstrual period. The possible luteolytic effect of the drug was not clearly implicated as the cause of the abortion. Another one of the reported cases had similar estradiol and progesterone levels at the same stage and the pregnancy went uneventfully to term (Shulman et al, 1993). A similar circumstance resulting in the birth of a healthy boy has been reported (Gartner et al, 1997).
2) TRIPTORELIN: Pregnancies occurring during treatment with triptorelin have generally resulted in uncomplicated delivery of normal babies. Of 47 pregnancies occurring during treatment with long-acting triptorelin (3.75 mg once per 28 days), there were 38 normal babies and 10 abortions (Taskin et al, 1999; Chardonnens et al, 1998). In 3 pregnancies occurring during short-acting triptorelin treatment (0.1 mg daily), there were 4 normal babies and no abortions (Chardonnens et al, 1998). Investigators caution that possible effects on fetal endocrine organs are as yet unknown.

D) ANIMAL STUDIES

1) GOSERELIN: Doses equal to or greater than 2 and 20 mcg/kg/day (approximately 0.1 and 2 times the daily maximum recommended human dose, respectively, on a mg/m(2) basis) administered to rats and rabbits, respectively, during organogenesis, have resulted in embryotoxicity and fetotoxicity, characterized by increased pregnancy loss, increased pre-implantation loss, increased resorption, and an increase in umbilical hernia (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005).
2) HISTRELIN: Increased fetal mortality and decreased fetal weights were noted in rats and rabbits following maternal administration of histrelin during gestation (Prod Info VANTAS(R) implant, 2005).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to luteinizing hormone-releasing hormone agonists during lactation in humans. Leuprolide use is contraindicated for use in nursing mothers (Prod Info LUPRON(R) DEPOT 3 Month formulation injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) DEPOT 4 Month Formulation injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) DEPOT injection, powder, lyophilized, for suspension, 2010; Prod Info LUPRON(R) injection, 2008; Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info SYNAREL(R) nasal solution, 2005).

3.20.5)

A) FERTILITY SUPPRESSION, REVERSIBLE

1) Clinical studies of leuprolide and similar analogs showed reversibility of fertility suppression in adult (at least 18 years old) humans upon drug discontinuation after continuous dosing periods of up to 24 weeks (Prod Info LUPRON DEPOT(R) 7.5 mg intramuscular injection, 2011).

B) ANIMAL STUDIES

1) LEUPROLIDE: Studies in male and female rats showed atrophy of the reproductive organs and suppression of reproductive function were produced with leuprolide as a monthly depot formulation for up to 3 months at doses of 0.024, 0.24, and 2.4 mg/kg (approximately 1/30 the human dose). After treatment discontinuation, these changes were reversible (Prod Info LUPRON DEPOT(R) 7.5 mg intramuscular injection, 2011).
2) GOSERELIN: Studies in male rats found that goserelin produced changes consistent with gonadal suppression as a result of its endocrine action, including decreased weight and atrophic histological changes in the testes, epididymis, seminal vesicle, and prostate gland with complete suppression of spermatogenesis (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005). In female rats, suppression of ovarian function resulted in decreased size and weight of the ovaries and the secondary sex organs. Also, follicular development was arrested at the antral stage and the corpora lutea were reduced in size and number (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005).

Carcinogenicity

3.21.2)

A) GOSERELIN

1) At the time of this review, the manufacturer did not report any carcinogenic potential.

3.21.3)

A) UTERINE LEIOMYOMA

1) GOSERELIN: Two women developed massive lymphocytic infiltration of uterine leiomyomas following goserelin implant therapy . Both women (53 years old and 47 years old) received goserelin before routine hysterectomy. The leiomyomas were heavily infiltrated by mature lymphocytes of T-cell phenotype with associated myocyte degenerative changes present (Bardsley et al, 1998).

3.21.4)

A) PITUITARY ADENOMAS AND SARCOMA

1) GOSERELIN

a) RATS: An increased rate of pituitary adenomas occurred with subQ implantation of goserelin of 80 and 150 mcg/kg doses in male rats, and 50 and 100 mcg/kg doses in female rats, once every 4 weeks for 1 year, and 23 weeks of recovery. Increased incidence of pituitary adenomas also occurred with subQ implants of similar goserelin doses in rats for 72 weeks in males, and 101 weeks in females. Human relevance of the rat pituitary adenomas has not been established (Prod Info ZOLADEX(R) subcutaneous implant, 2013).
b) MICE: Two years of doses up to 2400 mcg/kg/day every 3 weeks by subQ implants resulted in an increased incidence of histiocytic sarcoma of the femur and spinal column (Prod Info ZOLADEX(R) subcutaneous implant, 2013).

B) NEOPLASM

1) HISTRELIN

a) Administration of histrelin in rats for 2 years at doses of 5, 25, or 150 mcg/kg/day (up to 15 times the human dose) resulted in an increase in pituitary adenomas, an increase in pancreatic islet-cell adenomas in the female rats, an increase in stomach papillomas in male rats given high doses, and a non-dose related increase in Leydig-cell tumors. In mice, administration of histrelin for 18 months at doses of 20, 200, or 2000 mcg/kg/day (up to 200 times the human dose) resulted in an increase in mammary-gland adenocarcinomas in the female mice and an increase in histiocytic sarcomas in the female mice at the highest dose (Prod Info VANTAS(R) implant, 2005).

2) NAFARELIN

a) In studies conducted in rats and mice, use of nafarelin at proportionately high doses (100 to 500 mcg per kg of body weight, corresponding to 110 to 560 times the maximum recommended human intranasal dose) and for prolonged periods induced hyperplasia and/or neoplasia of endocrine organs (Prod Info SYNAREL(R) nasal solution, 2005). Increases in pancreatic islet cell adenomas, benign adrenal medullary tumors, Harderian gland tumors, benign testicular and ovarian tumors, pituitary adenomas, and carcinomas were noted in some animal treatment groups. No metastases of these tumors were observed (Prod Info SYNAREL(R) nasal solution, 2005).

3) TRIPTORELIN

a) The incidence of benign and malignant pituitary tumors and histiosarcomas, as well as mortality, increased with increased doses in rats given 120, 600, and 3000 mcg/kg of triptorelin (0.3, 2 and 8 times, respectively, the recommended human therapeutic dose [based on body surface area]) over 13 to 19 months. No oncogenic effect was noted in mice given up to 6000 mcg/kg of triptorelin (approximately 8 times the human therapeutic dose [based on body surface area]) every 28 days for 18 months (Prod Info TRELSTAR(R) LA IM injection, 2005).

C) ADENOMA

1) LEUPROLIDE: Studies in rats for 2 years at daily subcutaneous doses of 0.6 to 4 mg/kg (4 to 24 mg/m(2), 50 to 300 times the daily human exposure based on body surface area) found an increased incidence of benign pituitary hyperplasia and benign pituitary adenomas at 24 months in the rats. Also, there was a significant, but not dose-related, increase of pancreatic islet-cell adenomas in female rats and, at the lower dose, interstitial cell adenomas in the testes of male rats (Prod Info LUPRON DEPOT(R) subcutaneous injection, 2006; Prod Info VIADUR(R) subcutaneous implant, 2005).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
B) Monitor serum electrolytes in patients with significant vomiting.
C) Monitor hepatic enzymes in symptomatic patients.
D) Monitor for evidence of ovarian hyperstimulation (pelvic pain, bloating) as clinically indicated.
E) Obtain a pelvic ultrasound if ovarian hyperstimulation is a concern.

4.1.2)

A) Monitor serum electrolytes in patients with significant vomiting.
B) Monitor hepatic enzymes in symptomatic patients.

4.1.4)

A) OTHER

1) Monitor for evidence of ovarian hyperstimulation (pelvic pain, bloating) as clinically indicated.
2) Obtain a pelvic ultrasound if ovarian hyperstimulation is a concern.

Treatment

Life Support

A)

Patient Disposition

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

A) ADMISSION CRITERIA: Symptomatic patients requiring ongoing supportive care may need admission. Patients with evidence of ovarian hyperstimulation syndrome may require admission.

6.3.2.2) HOME CRITERIA/PARENTERAL

A) HOME CRITERIA: Patients with unintentional exposure may be observed at home if asymptomatic.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) CONSULT CRITERIA: Severe poisoning does not usually occur with these agents; however, if concerned about ovarian hyperstimulation syndrome, consult an obstetrician/gynecologist or specialist in reproductive medicine.

6.3.2.5) OBSERVATION CRITERIA/PARENTERAL

A) OBSERVATION CRITERIA: Symptomatic patients with uncontrollable nausea, vomiting, or abdominal pain should be evaluated in a healthcare facility. Patients may be discharged if asymptomatic 6 hours after exposure.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) Gastrointestinal decontamination is not indicated since these medications are administered via the intramuscular or subcutaneous route or intranasally.

Abstracts

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) GOSERELIN ACETATE

a) ADVANCED PROSTATE CANCER (PALLIATIVE TREATMENT): The recommended dosage regimen is a 3.6-mg implant administered subcutaneously every 28 days or a 10.8-mg implant administered subcutaneously every 12 weeks for long-term therapy (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info ZOLADEX(R) 10.8 mg implant, 2005).
b) PROSTATE CANCER (STAGE B2-C): In combination with flutamide, the recommended dosage regimen is a 3.6-mg implant administered subcutaneously followed in 28 days by subcutaneous administration of a 10.8-mg implant. This regimen is initiated 8 weeks prior to radiotherapy. An alternative regimen is 4 injections of 3.6 mg administered subcutaneously at 28-day intervals, 2 injections administered prior to radiotherapy and 2 injections administered during radiotherapy (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005).
c) ADVANCED BREAST CANCER (PALLIATIVE TREATMENT): The recommended dosage regimen is a 3.6-mg implant administered subcutaneously every 28 days for long-term therapy (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005).
d) ENDOMETRIOSIS: The recommended dosage regimen is a 3.6 mg implant administered subcutaneously every 28 days for up to 6 months (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005).

2) HISTRELIN ACETATE

a) ADVANCED PROSTATE CANCER (PALLIATIVE TREATMENT): The recommended dosage regimen is a 50-mg implant inserted subcutaneously for 12 months. After 12 months of therapy, the implant must be removed and another implant can be inserted in order to continue therapy (Prod Info VANTAS(R) implant, 2005).

3) LEUPROLIDE ACETATE

a) ADVANCED PROSTATE CANCER (PALLIATIVE TREATMENT)

1) SUBQ INJECTION: 1 mg SubQ once daily (Prod Info LUPRON(R) injection, 2008)
2) DEPOT 6-MONTH IM INJECTION: 45 mg depot IM once every 24 weeks; usually continued upon development of metastatic castration-resistant prostate cancer (Prod Info LUPRON DEPOT intramuscular injection depot suspension, 2016)
3) DEPOT 4-MONTH IM INJECTION: 30 mg depot IM once every 16 weeks; usually continued upon development of metastatic castration-resistant prostate cancer (Prod Info LUPRON DEPOT intramuscular injection depot suspension, 2016)
4) DEPOT 3-MONTH IM INJECTION: 22.5 mg depot IM once every 12 weeks; usually continued upon development of metastatic castration-resistant prostate cancer (Prod Info LUPRON DEPOT intramuscular injection depot suspension, 2016)
5) DEPOT 1-MONTH IM INJECTION: 7.5 mg depot IM once every 4 weeks; usually continued upon development of metastatic castration-resistant prostate cancer (Prod Info LUPRON DEPOT intramuscular injection depot suspension, 2016)
6) DEPOT 1-MONTH SUBQ INJECTION: 7.5 mg Eligard(R) SUBQ depot injection once monthly (Prod Info ELIGARD(R) subcutaneous injection suspension, 2016)
7) DEPOT 3-MONTH SUBQ INJECTION: 22.5 mg Eligard(R) SUBQ depot injection once every 3 months (Prod Info ELIGARD(R) subcutaneous injection suspension, 2016)
8) DEPOT 4-MONTH SUBQ INJECTION: 30 mg Eligard(R) SUBQ depot injection once every 4 months (Prod Info ELIGARD(R) subcutaneous injection suspension, 2016)
9) DEPOT 6-MONTH SUBQ INJECTION: 45 mg Eligard(R) SUBQ depot injection once every 6 months (Prod Info ELIGARD(R) subcutaneous injection suspension, 2016)
10) SUBQ IMPLANT: One Viadur(R) implant (65 mg leuprolide) inserted SUBQ in inner area of upper arm every 12 months (Prod Info VIADUR(R) subcutaneous implant, 2005)

b) ENDOMETRIOSIS: 3.75 mg IM as a depot injection administered once monthly for 6 months or 11.25 mg IM as a depot injection administered every 3 months for 6 months (Prod Info LUPRON DEPOT(R) injection suspension, 2005).
c) UTERINE LEIOMYOMA (FIBROIDS): 3.75 mg IM depot injection once monthly for up to 3 months or 11.25 mg IM 3-month depot injection for one dose (Prod Info LUPRON DEPOT(R) injection suspension, 2005).

4) LEUPROLIDE ACETATE/NORETHINDRONE ACETATE

a) ENDOMETRIOSIS: Leuprolide acetate 3.75 mg IM once monthly for up to 6 months OR 11.25 mg IM every 3 months for up to 2 doses (6 months), PLUS norethindrone acetate 5 mg orally once daily for up to 6 months; if symptoms recur after first course of therapy, patient may undergo an additional 6 month course; total treatment duration should not exceed 12 months (Prod Info LUPANETA PACK intramuscular injection powder, oral tablets, 2012; Prod Info LUPANETA PACK intramuscular injection powder, oral tablets, 2012a)

5) LUTROPIN ALFA/FOLLITROPIN ALFA

a) Follitropin alfa 150 international units/lutropin alfa 75 international units (1 vial) SubQ daily; increase follitropin alfa dose if necessary by 37.5 to 75 international units after 7 to 14 day intervals (Prod Info Pergoveris subcutaneous injection solution, 2012)

6) NAFARELIN ACETATE

a) ENDOMETRIOSIS: The recommended dose is 1 spray (200 mcg) into 1 nostril in the morning and 1 spray (200 mcg) into the other nostril in the evening. If a clinical response has not been achieved, the dose may be increased to 800 mcg, administered as 1 spray into each nostril in the morning and 1 spray into each nostril in the evening. The maximum dose is 800 mcg/day and the recommended duration of therapy is 6 months (Prod Info SYNAREL(R) nasal solution, 2005a).

7) TRIPTORELIN PAMOATE

a) ADVANCED PROSTATE CANCER (PALLIATIVE TREATMENT): The recommended dosage regimen is 3.27 mg intramuscularly as a depot injection administered every month or 11.25 mg intramuscularly administered every 84 days (Prod Info TRELSTAR(R) DEPOT IM injection, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005).

7.2.2)

A) SPECIFIC SUBSTANCE

1) GOSERELIN ACETATE

a) Safety and efficacy have not been established in pediatric patients (Prod Info ZOLADEX(R) 3.6 mg acetate implant, 2005; Prod Info ZOLADEX(R) 10.8 mg implant, 2005).

2) HISTRELIN ACETATE

a) The currently available formulation of histrelin acetate (as a 50-mg implant) is contraindicated in pediatric patients (Prod Info VANTAS(R) implant, 2005).

3) LEUPROLIDE ACETATE

a) CENTRAL PRECOCIOUS PUBERTY

1) SUBQ SUSPENSION: Initially 50 mcg/kg/day SUBQ for one dose; if down-regulation is not achieved, repeat doses titrated upward by 10 mcg/kg/day; the final titrated dose is considered the maintenance dose (Prod Info LUPRON(R) subcutaneous injection, 2009)
2) FOR DEPOT IM 1-MONTH SUSPENSION: 7.5 mg IM once every month in children weighing 25 kg or less; 11.25 mg IM once every month in children weighing more than 25 kg to 37.5 kg; and 15 mg IM once every month in children weighing greater than 37.5 kg; the dose can be titrated upward by to the next available higher dose as needed; dose may also be adjusted with changes in body weight (Prod Info LUPRON DEPOT-PED IM injection, powder, lyophilized, for depot suspension, 2011)
3) FOR DEPOT IM 3-MONTH SUSPENSION: 11.25 mg or 30 mg IM every 3 months (12 weeks) (Prod Info LUPRON DEPOT-PED 3 month intramuscular injection powder lyophilized for suspension, 2011)

4) LEUPROLIDE ACETATE/NORETHINDRONE ACETATE

a) Safety and efficacy have not been established in pediatric patients (Prod Info LUPANETA PACK intramuscular injection powder, oral tablets, 2012; Prod Info LUPANETA PACK intramuscular injection powder, oral tablets, 2012a).

5) NAFARELIN ACETATE

a) CENTRAL PRECOCIOUS PUBERTY: The recommended dose is 2 sprays (400 mcg) into each nostril in the morning and 2 sprays (400 mcg) into each nostril in the evening (for a total of 1600 mcg). The dose may be increased to 1800 mcg/day (3 sprays into alternating nostrils 3 times daily) if needed (Prod Info SYNAREL(R) nasal solution, 2005a).

6) TRIPTORELIN PAMOATE

a) Safety and efficacy have not been established in pediatric patients (Prod Info TRELSTAR(R) DEPOT IM injection, 2005; Prod Info TRELSTAR(R) LA IM injection, 2005).

Maximum Tolerated Exposure

A)

1) LEUPROLIDE - In clinical trials, daily subcutaneous leuprolide was administered to patients with prostate cancer. Doses up to 20 mg/day for up to 2 years did not result in any differences in adverse effects as compared with patients who were given doses of 1 mg/day (Prod Info LUPRON DEPOT(R) 3 month injection suspension, 2005).

Toxicity Information

7.7.1)

A) BUSERELIN ACETATE

1) LD50- (ORAL)MOUSE:

a) >1 g/kg (RTECS, 2006)

2) LD50- (SUBCUTANEOUS)MOUSE:

a) >1 g/kg (RTECS, 2006)

3) LD50- (ORAL)RAT:

a) >400 mg/kg (RTECS, 2006)

4) LD50- (SUBCUTANEOUS)RAT:

a) >500 mg/kg (RTECS, 2006)

B) GONADORELIN ACETATE

1) LD50- (ORAL)MOUSE:

a) >4 g/kg (RTECS, 2006)

2) LD50- (SUBCUTANEOUS)MOUSE:

a) >3 g/kg (RTECS, 2006)

3) LD50- (ORAL)RAT:

a) >3 g/kg (RTECS, 2006)

4) LD50- (SUBCUTANEOUS)RAT:

a) >2 g/kg (RTECS, 2006)

C) GOSERELIN ACETATE
D) LEUPROLIDE ACETATE

1) LD50- (INTRAMUSCULAR)MOUSE:

a) >2 g/kg (RTECS, 2006)

2) LD50- (INTRAPERITONEAL)MOUSE:

a) >5 g/kg (RTECS, 2006)

3) LD50- (ORAL)MOUSE:

a) >5 g/kg (RTECS, 2006)

4) LD50- (SUBCUTANEOUS)MOUSE:

a) >5 g/kg (RTECS, 2006)

5) LD50- (INTRAMUSCULAR)RAT:

a) >2 g/kg (RTECS, 2006)

6) LD50- (INTRAPERITONEAL)RAT:

a) >5 g/kg (RTECS, 2006)

7) LD50- (ORAL)RAT:

a) >5 g/kg (RTECS, 2006)

8) LD50- (SUBCUTANEOUS)RAT:

a) >5 g/kg (RTECS, 2006)

E) NAFARELIN ACETATE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) >500 mcg/kg (RTECS, 2006)

2) LD50- (ORAL)MOUSE:

a) >100 mg/kg (RTECS, 2006)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) >500 mcg/kg (RTECS, 2006)

4) LD50- (INTRAPERITONEAL)RAT:

a) 500 mcg/kg (RTECS, 2006)

5) LD50- (ORAL)RAT:

a) >50 mg/kg (RTECS, 2006)

6) LD50- (SUBCUTANEOUS)RAT:

a) 500 mcg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Physicochemical

Physical Characteristics

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C)

D)

E)

Molecular Weight

A)

B)

C)

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E)

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I)

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L)

Animal Toxicology

References

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LUTEINIZING HORMONE RELEASING HORMONE AGONISTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography