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Leuprolide (Systemic)



INN:

Leuprorelin

BAN:
Leuprorelin

VA CLASSIFICATION
Primary: HS900
Secondary: AN500

Commonly used brand name(s): Lupron; Lupron Depot; Lupron Depot-3 Month 11.25 mg; Lupron Depot-3 Month 22.5 mg; Lupron Depot-4 Month 30 mg; Lupron Depot-Ped; Lupron-3 Month SR Depot 22.5 mg; Viadur.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Gonadotropin-releasing hormone analog—

antiendometriotic agent—

antineoplastic—

gonadotropin inhibitor—

Indications
Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anemia due to uterine leiomyomas (treatment)1—Leuprolide, in conjunction with iron supplement therapy, is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomas (fibroids). Because some patients respond to iron supplementation alone, a 1-month trial period with iron should be considered prior to initiation of leuprolide therapy. Leuprolide may then be added if the response to iron supplementation is inadequate{08}{13}.

Carcinoma, prostatic (treatment)—Leuprolide is indicated for the palliative treatment of advanced prostatic cancer, especially as an alternative to orchiectomy or estrogen administration{04}{06} {07}{09}{11}{14}{20}.

Endometriosis (treatment)—Leuprolide is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions {08}{13}.

Puberty, precocious, central (treatment)—Leuprolide is indicated for the treatment of central precocious puberty (CPP, idiopathic or neurogenic) in children with the onset of secondary sexual characteristics before the age of 8 years in females and 9 years in males. Prior to initiation of leuprolide therapy, clinical diagnosis should be confirmed by a prepubertal response to a gonadorelin stimulation test and by bone age that is advanced 1 year beyond the chronological age.{01} {15} Diagnosis of CPP should be confirmed before initiation of treatment with leuprolide by measuring serum sex steroids, height and weight, and basal gonadotropin levels, and by testing stimulation response to gonadorelin, assessing diagnostic imaging of the brain (including pituitary and hypothalamus), and performing pelvic ultrasound examinations{01}.
—Before beginning treatment for CPP with leuprolide, it is especially important to confirm that the patient is willing to comply with dosing requirements and the frequent monitoring required by the physician during the first 6 to 8 weeks of treatment to assure that suppression of gonadal-pituitary function is rapid{01}.

[Carcinoma, breast (treatment)]1—Leuprolide is indicated in the palliative treatment of advanced breast carcinoma in premenopausal and perimenopausal women. {04}{11}{12}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Pharmacokinetic studies of leuprolide use in children have not been done {01}.


Physicochemical characteristics:
Source—
    Synthetic gonadotropin-releasing hormone (GnRH) analog{01} {06}{07}{08}{09} {13}{14}{15}{20}.
Molecular weight—
    Leuprolide acetate: 1269.48{05}

Mechanism of action/Effect:

Like naturally occurring luteinizing hormone–releasing hormone (LHRH), initial {02} or intermittent administration of leuprolide stimulates release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary {06} {07} {09} {11} {14}.

Prostatic carcinoma—LH and FSH release from the anterior pituitary transiently increases testosterone and dihydrotestosterone concentrations in males {06}{07}{09}{14}{20}. However, continuous administration of leuprolide in the treatment of prostatic carcinoma suppresses secretion of gonadotropin-releasing hormone, with a resultant fall in testosterone concentrations and a pharmacologic castration {06}{09}{14}{20}.

Anemia due to uterine leiomyomas; endometriosis; or breast carcinoma—Initial stimulation of gonadotropins from the anterior pituitary is followed by prolonged suppression {08}. Gonadotropin release from the anterior pituitary transiently increases estrone and estradiol concentrations in premenopausal females {06} {07} {09}. However, continuous administration of leuprolide produces a decrease in estradiol, estrone, {06} {07} {08} {09} {11} {14} and progesterone {11} concentrations to postmenopausal levels. As a consequence of suppression of ovarian function, both normal and ectopic endometrial tissues become inactive and atrophic {07}. As a result, amenorrhea occurs {08}.

Central precocious puberty—After an initial stimulation of gonadotropins and increase in the rate of pubertal development, testosterone and estradiol concentrations in males and females, respectively, decrease to prepubertal levels with continuous administration of therapeutic doses of leuprolide in children. Stimulated and basal gonadotropin concentrations also are reduced to prepubertal levels. As a result, menses stop, reproductive organ development decreases, and bone age velocity approaches normal, improving the child's chance of attaining the predicted adult height {01}. Upon discontinuation of leuprolide, gonadotropins return to pubertal levels and natural maturation resumes. {01} {15}


Other actions/effects:

Leuprolide also has some androgenic effects in females {08}.

Absorption:

Bioavailability after intramuscular injection of the depot formulation is estimated to be about 90%{08}.

The leuprolide acetate implant delivers 120 micrograms of leuprolide acetate per day over 12 months.{20}

Distribution:

The mean steady-state volume of distribution following a single intravenous dose in healthy male volunteers was 27 L{06}{08} {09}{13}{14}{15}{20}.

Protein binding:

Moderate (46%) {06}{08}{09} {13}{14}{15}{20}.

Biotransformation:

Metabolized to smaller inactive peptides, Metabolite I (a pentapeptide), Metabolites II and III (tripeptides), and Metabolite IV (a dipeptide) {06} {08} {09} {13} {14}.

Half-life:

Approximately 3 hours following a 1-mg intravenous dose in healthy male volunteers {06} {08} {09} {13} {14} {15}.

Onset of action:

Transient increases in testosterone and estradiol concentrations occur within the first week of therapy; a decline to castrate and postmenopausal levels, respectively, occurs within 2 to 4 weeks{06}{07}{09} {11}{14}{20}.

Time to peak concentration:

3.75-mg depot—4 hours {08}.

7.5-mg depot—4 hours {09} {15}.

22.5-mg depot—4 hours {06}.

Peak plasma concentration

3.75-mg depot—4.6 to 10.2 nanograms per mL (nanograms/mL) {08}.

7.5-mg depot—20 nanograms/mL {09} {15}.

22.5-mg depot—48.9 nanograms/mL {06}.

Steady-state serum concentration

After insertion of a leuprolide acetate implant, the mean serum leuprolide concentrations were 16.9 ng/mL at 4 hours and 2.4 ng/mL at 24 hours. Thereafter, leuprolide was released at a constant rate. Mean serum leuprolide concentrations were maintained at 0.9 ng/mL for 12 months. {20}

Time to peak effect:

Amenorrhea—Usually occurs after 1 to 2 months of therapy {08} {13}.

Prostatic carcinoma—Usually occurs after 2 to 4 weeks of therapy {20}

Duration of action:

Pituitary-gonadal system—Normal function is usually restored within 4 to 12 weeks after therapy is withdrawn {08}.

Amenorrhea—Cyclic bleeding usually returns within 60 to 90 days after therapy is withdrawn {08} {13}.

Elimination:
    Less than 5% of a 3.75-mg dose was recovered in the urine as parent drug and Metabolite I {06} {08} {09} {13} {14} {15}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to gonadorelin (GnRH), to components of any product, or to gonadotropin-releasing hormone analogs (GnRHa), such as buserelin, goserelin, histrelin, and nafarelin, may be sensitive to leuprolide also{01}{08}{20}.

Carcinogenicity

Adults treated with doses of leuprolide as high as 10 mg a day for up to 3 years and 20 mg a day for up to 2 years have not shown clinical abnormalities of the pituitary {01}.

Studies in rats and mice for 2 years at daily subcutaneous doses of 0.6 to 4 mg per kg of body weight (mg/kg) and up to 60 mg/kg, respectively, found an increased incidence of benign pituitary hyperplasia and benign pituitary adenomas at 24 months in the rats {01}{06}{07}{08} {09}{13}{14}{15}{20}. 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{01}{20}.

Mutagenicity

Mutagenicity studies in bacterial and mammalian systems found no evidence of mutagenic effects{06}{07}{08} {09}{13}{14}{20}.

Pregnancy/Reproduction
Fertility—
In adult males: Suppression of testosterone secretion results in impairment of fertility. However, studies in adults administered leuprolide and similar analogs have shown reversal of fertility suppression when the medications were discontinued after continuous administration for periods of up to 24 weeks {06}{09}{13}{14}.

In adult females: Leuprolide usually induces anovulation and amenorrhea. This effect is reversible and the average time to return of menses is about 60 to 90 days following withdrawal of therapy. A nonhormonal contraceptive method should be used during leuprolide therapy{08}{13}.

Male and female children: Long-term posttreatment follow-up studies of fertility in children treated for central precocious puberty (CPP) have not been done {01}.

Animal studies of adult and prepubertal rats and monkeys given leuprolide or other GnRH analogs showed functional reproductive recovery. Immature male and female rats given leuprolide in one study were normal when compared with controls, even though the histologic investigation showed that tubular degeneration in the testes occurred after a recovery period. The offspring of both sexes appeared normal.{01}

Pregnancy—
Leuprolide is not recommended for use during pregnancy; spontaneous abortion may occur {01}{06}{07}{08} {09}{13}{14}{15}{20}.

Studies in rabbits at doses of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human adult dose; 1/1200 to 1/12 the human pediatric dose) on day 6 of pregnancy found a dose-related increase in major fetal abnormalities; these effects did not occur at similar doses in rats. The two higher doses in rabbits and the highest dose in rats were associated with increased fetal mortality and decreased fetal weights{01} {06} {07} {08} {09} {13} {15}.

FDA Pregnancy Category X{01} {06}{07}{08} {09} {13}{14}{15}{20}.

Breast-feeding

It is not known whether leuprolide passes into breast milk. However, because of potential adverse effects in the infant, breast-feeding is usually not recommended during treatment with leuprolide {01} {08} {13} {15}.

Pediatrics

Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of leuprolide in children.


Geriatrics


Appropriate studies on the relationship of age to the effects of leuprolide have not been performed in the geriatric population. However, this medication is frequently used in elderly patients, especially for treatment of prostatic carcinoma, and geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Gonadal function testing and
» Pituitary gonadotropic function testing    (therapeutic doses of leuprolide suppress the pituitary-gonadal feedback regulatory system; baseline function usually is restored within 3 months after discontinuation of treatment{01}{06}{08} {09}{13}{14}{15}{20})

With physiology/laboratory test values
Acid phosphatase    (transient increases in values may occur early in treatment of prostatic carcinoma, but usually decrease to or near baseline by the fourth week {07})


Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH)    (values may be increased {08} {09} {13} {15})


Estradiol    (serum concentrations usually are increased during the first weeks of therapy in adult females but then decrease to postmenopausal levels {08} {13})


Low-density lipoprotein (LDL) cholesterol and
Total cholesterol and
Triglycerides    (concentrations may be increased {06} {08} {13})


Platelet counts and
White blood cell counts    (may decrease; platelet count decrease may be transient, returning to normal during treatment {08})


Testosterone    (serum concentrations are usually increased during the first week of therapy for prostatic carcinoma but then decrease; castrate levels are reached within 2 to 4 weeks {07} {14}{20})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Sensitivity to gonadorelin (synthetic gonadotropin-releasing hormone [GnRH]); gonadotropin-releasing hormone analogs (GnRHa), such as buserelin, goserelin, histrelin, leuprolide, and nafarelin; or benzyl alcohol {01} {08} {13} {14} {15}{20}
For treatment of endometriosis or of anemia due to uterine leiomyomas :
Conditions causing decrease in bone density or
Osteoporosis, or history of, or family history of    (hypoestrogenism-induced loss of bone mineral density may occur in females treated with leuprolide and may be irreversible; major risk factors include chronic alcohol and/or tobacco abuse, family history of severe osteoporosis, and chronic use of medications, such as anticonvulsants or corticosteroids, that decrease bone mineral density; leuprolide should be used with caution in these patients {08})


» Uterine bleeding, undiagnosed abnormal    (use of leuprolide may delay diagnosis {08} {13})


For treatment of prostatic carcinoma:
» Urinary tract obstruction or history of    (existing urinary tract obstruction should be treated before beginning treatment with leuprolide; for patients with a history of urinary tract obstruction, there is an increased incidence of disease flare during initial leuprolide treatment because of the initial increase in serum testosterone concentrations; close monitoring is recommended during the first month of treatment; catheterization may be necessary on occurrence {06}{07}{09} {14}{20})


» Vertebral metastases    (worsening of symptoms during first few weeks of leuprolide therapy, with risk of neurologic problems, including paralysis{06}{07} {09}{14}{20})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Bone density assessment    (recommended as needed to monitor patient's response during long-term use of leuprolide, including treatment of endometriosis for longer than 6 months {16})


For treatment of central precocious puberty
Bone linear growth velocity and bone age velocity determinations and
Imaging studies    (recommended prior to treatment initiation and periodically during treatment, beginning 3 to 6 months after treatment initiation; diagnostic imaging studies should include radiography of the left hand and wrist [or non-dominate hand and wrist] for bone age determination, pelvic ultrasonography, and magnetic resonance imaging of the brain {01})


Dehydroepiandrosterone concentrations, serum and/or
Estradiol concentrations, serum and/or
Follicle-stimulating hormone concentrations, serum and/or
Human chorionic gonadotropin concentrations, serum and/or
Hydroxyprogesterone concentrations, serum and/or
Luteinizing hormone concentrations, serum and/or
Prolactin concentrations, serum and/or
Testosterone concentrations, serum    (recommended prior to treatment initiation to establish prepubertal gonadotropin response {01}. If gonadal-pituitary function suppression is not apparent within 6 to 8 weeks after therapy with leuprolide is initiated and lack of patient compliance is ruled out, leuprolide should be discontinued and the diagnosis of gonadotropin-independent sexual precocity should be reconsidered. Other possible causes of sexual precocity include adrenal hyperplasia, testoxicosis, and hypothalamic or testicular tumors {01})


Gonadotropin-releasing hormone stimulation test    (recommended prior to treatment initiation to establish prepubertal gonadotropin response {01})


Pregnancy test    (recommended if treatment is not started during menstruation and in patients with irregular menstrual cycles {01})


For treatment of endometriosis
Pregnancy test    (recommended for females of reproductive potential if treatment is not started during menstruation, if irregular menstrual cycles exist, or if a scheduled dose is delayed {08})


For treatment of prostatic carcinoma
Acid phosphatase concentrations, plasma prostatic {06} {07} {09} or serum and/or
Prostate-specific antigen (PSA) concentrations, serum {10} {14} and/or
Testosterone concentrations, serum    (recommended at periodic intervals to monitor response{06} {07}{09}{14}{20})


Bone scans    (recommended as needed to monitor response in patients at risk for vertebral metastases{16})


Imaging studies    (intravenous pyelogram, computerized tomography [CT] scan, and/or ultrasonography may be used to diagnose or assess patients at risk for obstructive uropathy; these are especially useful during the first week of therapy {16})




Side/Adverse Effects

Note: Many of the side/adverse effects of leuprolide are related to hypoestrogenism in females and hypotestosteronism in males{07} {08}{11}{20}. The reversibility of clinical hypogonadism produced by leuprolide has not been established for long-term use{16}.
There is a risk of increased loss of vertebral trabecular bone density during treatment for endometriosis or for anemia due to uterine leiomyomas; this loss may be irreversible {08} {13}. However, the loss usually is small when the treatment period is limited to 3 months (for fibroids) or 6 months (for endometriosis), except in patients with existing risk factors (e.g., history of osteoporosis) {08}. Compared to pretreatment bone density values, bone density values measured by dual energy x-ray absorptiometry (DEXA) decreased by 3.9% for patients treated for endometriosis at 6 months; a 12-month measurement, 6 months after leuprolide discontinuation, showed the decrease as 2% in these patients. Decreased bone density also has been reported in men who have had orchiectomy or who have been treated with a gonadotropin–releasing hormone analog. {14}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent—> 5%
In adult females and males
    
Cardiac arrhythmias or palpitations {07}{08}{09}{13}{14}(fast or irregular heartbeat )—up to 19% in males


Incidence rare—< 5%
In adult females and males
    
Anaphylaxis {06}{08}{09}{13}{14}{15}{20}(changes in facial skin color ; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash, hives, and/or itching; sudden, severe decrease in blood pressure and collapse)
    
bone, muscle, or joint pain, continuing
    
paresthesias {07}{08}{09}{13}{14}{20}(numbness or tingling of hands or feet)
    
syncope {08}(fainting)

In adult females only
    
Androgenic effects {08}(deepening of voice; increased hair growth)
    
personality or behavioral changes ( anxiety; mental depression; mood changes; nervousness){08}{13}

In adult males only
    
Angina or myocardial infarction ( pains in chest){07}{09}
    
pulmonary embolism (sudden shortness of breath)
    
thrombophlebitis {07}{14}(pains in groin or legs, especially calves of legs)

In pediatric females and males
    
Body pain {01}{15}
    
injection site reactions {01}{15}(burning, itching, redness, or swelling at place of injection)
    
skin rash {01}{15}

In pediatric females—expected within first few weeks
    
Uterine bleeding, continuing ( vaginal bleeding){01}{15}
    
vaginal discharge, continuing {01}{15}( white vaginal discharge)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—> 50% In adult females and males
    
Hot flashes {06}{07}{08}{09}{11}{13}{14}{20}(sudden sweating and feelings of warmth)

In adult females only
    
Amenorrhea (stopping of menstrual periods), or spotting ( light, irregular vaginal bleeding)


Incidence less frequent–5 to 13%
In adult females and males
    
Blurred vision {07}{08}
    
decreased libido {08}{13}(decreased interest in sexual intercourse)
    
dizziness {06}{07}{08}{13}{14}
    
edema {01}{06}{07}{08}{09}{13}{14}{15}{20}(swelling of feet or lower legs)
    
headache {01}{06}{07}{08}{13}{14}{15}{20}
    
injection site reaction {06}{07}{08}{09}{13}{14}{15}{20}(bleeding, bruising, burning, itching, pain, redness, or swelling at place of injection )
    
nausea or vomiting {01}{07}{08}{09}{11}{13}{15}
    
swelling or increased tenderness of breasts {08}{20}
    
trouble in sleeping {06}{07}{08}{09}{13}{14}
    
weight gain {01}{07}{08}{09}{13}{15}{20}

In adult females only
    
Endometriotic disease flare, transient (pelvic pain){08}{13}{15}
    
vaginitis {01}{08}{13}{15}(burning, dryness, or itching of vagina)

Note: An endometriotic disease flare, with a transient increase in symptoms (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, induration), may occur shortly after initiation of therapy for endometriosis as a result of the temporary increase in serum estradiol {08}.


In adult males only
    
Constipation {07}
    
decreased size of testicles {06}{07}{09}{14}{20}
    
prostatic carcinoma disease flare, transient (bone pain){06}{07}{09}{14}{15}{20}
    
impotence {06}{07}{09}{14}{20}(inability to have or keep an erection)

Note: A prostatic carcinoma disease flare, with a transient, sometimes severe, increase in bone or tumor pain, may occur shortly after initiation of therapy for prostatic carcinoma, usually associated with the increase in serum testosterone, but usually subsides with continued leuprolide treatment. Analgesics may be required during this time. Other signs and symptoms of prostatic carcinoma, including difficult urination and spinal compression {09} {14}, may also worsen transiently. In addition, worsening of neurologic signs and symptoms in patients with vertebral metastases may result in temporary weakness and paresthesias of the lower extremities {03} {06} {07} {14}; paralysis, with or without fatal complications, is possible {07} {09}{20}.







Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Leuprolide (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to gonadorelin (GnRH), leuprolide or other GnRH analogs (GnRHa), or to other ingredients in the product's formulation, such as benzyl alcohol

Pregnancy/reproduction—For females and males: May impair fertility by suppressing sperm production in males and causing anovulation in most females, usually reversible after discontinuation

For females: Not recommended for use during pregnancy; may cause spontaneous abortion, causes birth defects in animals





Breast-feeding—Not recommended for use in nursing mothers
Other medical problems, especially undiagnosed abnormal vaginal bleeding (for endometriosis or uterine leiomyomas), urinary tract obstruction (for prostatic carcinoma), or vertebral metastases (for prostatic carcinoma)

Proper use of this medication
» Carefully reading patient instruction sheet contained in package

Using disposable syringes provided in kit

» Importance of not using more or less medication than the amount prescribed

» Importance of continuing medication despite side effects

» Proper dosing
Missed dose:

• For daily dosing—Using as soon as remembered; not using if not remembered until next day; not doubling doses


• For monthly or every 3 to 12 months dosing—Receiving as soon as remembered; returning to normal dosing schedule


» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

For treatment of endometriosis or of anemia due to uterine leiomyomas
Possibility of amenorrhea or irregular menstrual periods; checking with physician if regular menstruation does not occur within 60 to 90 days after discontinuation of medication

Notifying physician if regular menstruation persists during treatment; however, missing one or more successive doses of leuprolide may result in breakthrough menstrual bleeding

Advisability of using nonhormonal forms of contraception during therapy; not using oral contraceptives

» Stopping medication and checking with physician if pregnancy is suspected


Side/adverse effects
Signs of potential side effects, especially cardiac arrhythmias or palpitations (adults); anaphylaxis (adults); bone, muscle, or joint pain (adults); paresthesias (adults); syncope (adults); androgenic effects in females (adults); personality or behavioral changes in females (adults); angina or myocardial infarction in males (adults); pulmonary embolism in males (adults); thrombophlebitis in males (adults); body pain (children); injection site reactions (children); skin rash (children); uterine bleeding in females, continuing (children); and vaginal discharge, continuing (children)


General Dosing Information
It is recommended that the intramuscular depot injection be administered by the physician {06} {08} {13} {14}. Parents or guardians may be instructed in how to give the subcutaneous injections at home to their child. Injection sites should be rotated periodically {01}.

Leuprolide has approximately 15 to 50 times the activity of naturally occurring luteinizing hormone–releasing hormone (LHRH), and 80 to 100 times that of gonadotropin–releasing hormone (gonadorelin).

For treatment of anemia due to uterine leiomyomas
Therapy should continue uninterrupted for 3 months. Re-treatment is not recommended. However, if re-treatment is contemplated, bone density should be assessed prior to beginning treatment to verify that values are in the normal range. {13}

For treatment of central precocious puberty
Dose must be individualized for each patient and titrated upward until patient's pituitary-gonadal axis is suppressed, according to clinical and/or laboratory parameters. Usually the dose that adequately suppresses the pituitary-gonadal axis is appropriate for the entire therapy; however, there are insufficient data to guide dosage adjustments as a child's weight changes, a special concern for children who started therapy at a very early age at a low dose {01}. Careful monitoring for suppression of the pituitary-gonadal axis is required, especially 1 or 2 months after treatment initiation or following changes in dose {01}.

If the patient responds and tolerates leuprolide therapy, treatment should continue until resumption of puberty is desired. Discontinuation of leuprolide therapy should be considered before the age of 11 years in females and 12 years in males {01} {15}. Normal function of pituitary-gonadal axis is restored within 4 to 12 weeks after treatment discontinuation {01}.

For treatment of endometriosis
It is recommended that therapy begin with the first day of the menstrual cycle after pregnancy has been ruled out.

Development of amenorrhea is usually evidence of a clinical response, although spotting or bleeding from the atrophic endometrium can still occur.

Therapy should continue uninterrupted for 6 months {08}. Re-treatment is not recommended. However, if re-treatment is contemplated, bone density should be assessed prior to beginning treatment to verify that values are in the normal range. {13}

For treatment of prostatic carcinoma
Patients receiving leuprolide should be under supervision of a physician experienced in cancer chemotherapy.

Isolated short-term worsening of neurologic symptoms may contribute to paralysis with or without fatal complications in patients with vertebral metastases. For patients at risk, therapy may be initiated with daily leuprolide injection for the first 2 weeks to observe patient reaction, since worsening of symptoms occasionally requires discontinuation of therapy and possible surgical intervention {16}.

For treatment of adverse effects
Recommended treatment:    • Bone pain—Mild oral analgesics with rest or, if severe, parenteral narcotics. Bone pain usually subsides after 2 weeks. {16}
   • Urinary obstruction, worsening of, in treatment of prostatic carcinoma—Catheterization {16}. Urinary obstruction usually disappears after the first week of leuprolide therapy. {16}



Parenteral Dosage Forms

LEUPROLIDE ACETATE IMPLANT

Usual adult dose
Carcinoma, prostatic
Subcutaneous implant, one implant per 12 months{20}

Note: The leuprolide acetate implant delivers approximately 120 micrograms of leuprolide acetate per day over 12 months.{20}



Usual pediatric dose
Safety and efficacy have not been established.{20}

Strength(s) usually available
U.S.—


65 mg (free base) per implant (Rx) [Viadur (dimethyl sulfoxide 104 mg) (sodium chloride) ( sodium carboxymethyl cellulose) (povidone) (magnesium stearate) (polyethylene glycol) (sterile water for injection){20}]

Packaging and storage:
Store at 25 ° C (77 ° F), excursions permitted to 15 to 30 ° C (59 to 86 ° F). {20}


LEUPROLIDE ACETATE INJECTION

Usual adult dose
Carcinoma, prostatic
Subcutaneous, 1 mg per day {07}.


Usual pediatric dose
Puberty, precocious, central
Subcutaneous, initially 50 mcg per kg of body weight per day as a single injection, increased as needed by increments of 10 mcg per kg of body weight per day to a maintenance dose {01}. Younger children require larger doses on a mcg per kg of body weight basis; dose should be increased as weight increases throughout treatment.{01}


Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Lupron (sodium chloride 6.3 mg) (benzyl alcohol 9 mg) (water for injection ){01}{07}]

Note: Packaging is labeled as Lupron 14 Day Patient Administration Kit (2.8 mL multiple dose vial and 1/2 cc 28-gauge 1/2-inch syringes) or Lupron 28 Day Patient Administration Kit (double the supplies of Lupron 14 Day Patient Administration Kit). Insulin syringes may be used also if volume is appropriately adjusted {01} {07}.


Canada—


5 mg per mL (Rx) [Lupron (benzyl alcohol){16}]

Note: Packaging includes multiple dose vial of 2.8 mL {16}.


Packaging and storage:
In U.S.: Store below 25 °C (77 °F), unless otherwise specified by manufacturer. In Canada: Store between 2 and 8 °C (36 and 46 °F) before dispensing and between 15 and 30 °C (59 and 86 °F) after dispensing, unless otherwise specified by manufacturer. Protect from freezing {01} {07}. Protect from light {01} {07}.

Stability:
Do not use if cloudy or discolored {01}.

Auxiliary labeling:
   • Do not freeze.


LEUPROLIDE ACETATE FOR INJECTION

Note: Due to different release characteristics, a fractional dose of the 3-month or 4-month depot formulations is not equivalent to the same dose of the 1-month depot formulation and should not be given in its place {08} {13}.


Usual adult dose
Anemia due to uterine leiomyomas1
Intramuscular, 3.75 mg once a month for a maximum duration of three months {08} or one 11.25-mg injection {13}.

Carcinoma, prostatic
Intramuscular, 7.5 mg once a month {09}, 22.5 mg once every three months (eighty-four days) {06}, or 30 mg every four months {14}.

Endometriosis
Intramuscular, 3.75 mg once a month {08} or 11.25 mg every three months {13} for a maximum duration of six months {08} {13}.


Usual pediatric dose
Puberty, precocious, central


Initial:
Intramuscular, 0.3 mg per kg of body weight every four weeks, using a minimum total dose of 7.5 mg every four weeks {17}.
For children weighing £ 25 kg—Intramuscular, 7.5 mg every four weeks {15}.

For children weighing 25 to 37.5 kg—Intramuscular, 11.25 mg every four weeks {15}.

For children weighing > 37.5 kg—Intramuscular, 15 mg every four weeks {15}.




Maintenance:
The dose may be increased as needed by increments of 3.75 mg every four weeks {15}, up to a maximum total dose of 15 mg every four weeks {17}.



Size(s) usually available:
U.S.—



1-month release formulation


3.75 mg vial [Lupron Depot{13}]


7.5 mg vial (Rx) [Lupron Depot{09}] [Lupron Depot-Ped{15}]


11.25 mg vial (Rx) [Lupron Depot-Ped{15}]


15 mg vial (Rx) [Lupron Depot-Ped{15}]

Note: Packaged as single-use vial kits for Lupron Depot 7.5 mg {09} and single-use vial kits and prefilled dual-chamber syringe kits for Lupron Depot 3.75 mg {08} {13} and for all pediatric formulations {15}. Kits include alcohol swabs and syringes. All packaging includes the diluent. Inactive ingredients may differ among products and their diluents. {01}




3-month release formulation


11.25 mg vial [Lupron Depot-3 Month 11.25 mg{13}]


22.5 mg vial (Rx) [Lupron Depot-3 Month 22.5 mg{06}]



4-month release formulation


30 mg vial (Rx) [Lupron Depot-4 Month 30 mg{14}]

Canada—



1-month release formulation


3.75 mg vial [Lupron Depot{13}]


7.5 mg vial (Rx) [Lupron Depot{09}]


11.25 mg vial (Rx) [Lupron Depot{17}]


15 mg vial (Rx) [Lupron Depot{17}]



3-month release formulation


22.5 mg vial (Rx) [Lupron-3 Month SR Depot 22.5 mg{16}]

Note: Packaging of single-use vial kits includes alcohol swabs and syringes. All packaging includes the diluent. Inactive ingredients may differ among products and their diluents.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer {08} {09}. Protect from freezing {06} {08} {09} {13} {14} {15}.

Preparation of dosage form:
Vial and ampule—Leuprolide acetate for injection is reconstituted with an appropriate volume of diluent provided by the manufacturer; the suspension should be shaken thoroughly to disperse particles evenly {06} {08} {09} {13} {14} {15}.

Prefilled dual-chamber syringe—For reconstitution, the manufacturer's instructions should be followed to release the diluent into the chamber of lyophilized microspheres. The suspension is then shaken gently to disperse the particles evenly. {08} {15}

Stability:
Since leuprolide for injection and the diluent contain no preservatives, the reconstituted suspension should be used immediately after preparation and any unused portion should be discarded {06} {08} {09} {13} {14} {15}.

Auxiliary labeling:
   • Do not freeze.
   • Shake well (after reconstitution).



Revised: 09/05/2000



References

Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

  1. Lupron injection for pediatric use package insert (TAP—US), Rev 04/96, Rec 04/01/98.
  1. Manufacturer comments, 8/85.
  1. Panel comments, 1988.
  1. Reviewers" responses to Hematologic-Oncologic Advisory Panel Memo #9 of 01/30/97.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1997. p. 414.
  1. Lupron Depot-3 month 22.5 mg package insert (TAP—US), Rev 03/97, Rec 08/01/97.
  1. Lupron injection package insert (TAP—US), Rev 04/96, Rec 08/01/97.
  1. Lupron Depot 3.75 mg package insert (TAP—US), Rev 04/97, Rec 08/01/97.
  1. Lupron Depot 7.5 mg package insert (TAP—US), Rev 06/97, Rec 08/01/97.
  1. Panel comments, 6/93.
  1. Erlichman C, Loprinzi CL. Pharmacology of cancer chemotherapy. Hormonal therapies. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 400-1.
  1. Breast cancer. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov.
  1. Lupron Depot-3 Month 11.25 mg package insert (TAP—US), Rev 03/97, Rec 08/01/97.
  1. Lupron Depot-4 Month 30 mg package insert (TAP—US), Rev 06/97, Rec 08/01/97.
  1. Lupron Depot-Ped package insert (TAP—US), Rev 04/97, Rec 08/01/97.
  1. Lupron Depot 7.5 mg and Lupron 3-month SR Depot 22.5 mg product monograph (Abbott—Canada), Rev 12/04/96, Rec 08/05/97.
  1. Lupron 5 mg/mL and Lupron Depot 3.75 mg/vial, 7.5 mg/vial, 11.25 mg/vial and 15 mg/vial product monograph (Abbott—Canada), Rev 02/12/96, Rec 08/05/97.
  1. Lupron Depot 3.75 mg/vial (1 month slow release) product monograph (Abbott—Canada), Rev 05/27/97, Rec 08/05/97.
  1. Lupron 5 mg/mL and Lupron Depot 7.5 mg/vial product monograph (Abbott—Canada), Rev 08/28/89, Rec 09/21/94.
  1. Product Information: Viadur™, leuprolide acetate implant. ALZA Corporation, Mountain View, CA (PI revised 2/2000) reviewed 8/2000.
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