Luprolex

Luprolex

leuprorelin

Manufacturer:

Takeda

Distributor:

Takeda
Full Prescribing Info
Contents
Leuprorelin acetate.
Description
Each vial contains 1.88 mg, 3.75 mg or 11.25 mg leuprorelin acetate as lyophilized microspheres.
Leuprorelin is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone.
3.75 mg: Leuprorelin is a long-acting GnRH analog. A single monthly injection of Leuprorelin (Luprolex) 3.75mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprorelin (Luprolex) is not active when given orally. Intramuscular injection provides plasma concentrations of leuprolide over a period of one month.
11.25 mg: Leuprorelin is a long-acting GnRH analog. A single monthly injection of Leuprorelin (Luprolex) 11.25mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at quarterly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprorelin (Luprolex) is not active when given orally. Intramuscular injection provides plasma concentrations of leuprolide over a period of three months.
Action
Pharmacology: Pharmacokinetics: 3.75 mg: Absorption: A single dose of Leuprorelin (Luprolex) 3.75 mg was administered by intramuscular injection to healthy female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprolide and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30ng/mL.
Distribution: The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism: In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.
Excretion: Following administration of Leuprorelin (Luprolex) 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.
Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.
Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been conducted with Leuprorelin (Luprolex). However, because Leuprorelin is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.
11.25 mg: Absorption: Following a single injection of the three month formulation of Leuprorelin (Luprolex) 11.25mg in female subjects, a mean plasma leuprolide concentration of 36.3ng/mL was observed at 4 hours. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing and mean levels then declined gradually to near the lower limit of detection by 12 weeks. The mean (± standard deviation) leuprolide concentration from 3 to 12 weeks was 0.23 ± 0.09 ng/mL. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.
Distribution: The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism: In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.
In a pharmacokinetic/pharmacodynamics study of endometriosis patients, intramuscular Leuprorelin (Luprolex) 11.25mg every 12 weeks or intramuscular Leuprorelin (Luprolex) 3.75mg every 4 weeks was administered for 24 weeks. There was no statistically significant difference in changes of serum estradiol concentration from baseline between the 2 treatment groups.
M-I plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.
Excretion: Following administration of Leuprorelin (Luprolex) 3.75mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.
Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.
Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been conducted with Leuprorelin (Luprolex). However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.
Indications/Uses
1.88 mg: Central precocious puberty, Uterine myoma/fibroids, Endometriosis.
3.75 mg: Endometriosis, Uterine myoma/fibroids, Premenopausal breast cancer, Prostate cancer.
In children: Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age).
11.25 mg: Endometriosis, Uterine myoma/fibroids, Premenopausal breast cancer, Prostate cancer, Central precocious puberty.
Dosage/Direction for Use
LUPROLEX Must Be Administered Under the Supervision of a Physician
1.88 mg: Luprolex 1.88 mg is to be given ONCE A MONTH.
Incorporated in a depot formulation, the lyophilized microspheres are to be reconstituted and administered as a single intramuscular/subcutaneous injection, in accordance with the following directions: 1. Using a syringe with a 23 gauge needle, withdraw 2 mL of diluent from the ampule, and inject it into the vial.
2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.
3. Withdraw the entire contents of the vial into the syringe and inject it at the time of reconstitution.
The suspension settles very quickly following reconstitutions, therefore, it is preferable that Luprolex be mixed and used immediately. Reshake suspension if settling occurs.
Although the potency of the reconstituted suspension has been shown to be stable for 24-hours, since the product does not contain a preservative, the suspension should be discarded if not used immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
3.75 mg: Leuprorelin (Luprolex) 3.75 mg is to be given ONCE A MONTH.
Incorporated in a depot formulation, the lyophilized microspheres are to be reconstituted and administered as a single intramuscular/subcutaneous injection, in accordance with the following directions: 1. Using a syringe with a 23 gauge needle, withdraw 2 mL of diluent from the ampule, and inject it into the vial.
2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.
3. Withdraw the entire contents of the vial into the syringe and inject it at the time of reconstitution.
The suspension settles very quickly following reconstitutions, therefore, it is preferable that Leuprorelin (Luprolex) to be mixed and used immediately. Reshake suspension if settling occurs.
Although the potency of the reconstituted suspension has been shown to be stable for 24-hours, since the product does not contain a preservative, the suspension should be discarded if not used immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
Pediatric Population: The treatment of children with leuprorelin acetate should be under the overall supervision of the pediatric endocrinologist.
The dosing scheme needs to be adapted individually.
The recommended starting dose is dependent on the body weight.
Children with a body weight >20 kg: 1 mL (3.75 mg leuprorelin acetate) suspension of 44.1 mg sustained-release microcapsules in 1 mL vehicle solution are administered once a month as a single subcutaneous injection.
Children with a body weight <20 kg: In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty: 0.5 mL (1.88 mg leuprorelin acetate) is administered once a month as a single subcutaneous injection.
The remainder of the suspension should be discarded. The child's weight gain should be monitored.
Depending on the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the LHRH test). The minimal effective monthly dose to be administered should then be determined by means of the LHRH test.
Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at higher than the recommended dosages. Therefore, in such cases, the medicinal product should be administered subcutaneously.
It is recommended to use the lowest volume possible for injections in children in order to decrease the inconvenience which is associated with the intramuscular/subcutaneous injection.
The duration of treatment depends on the clinical parameters at the start of treatment or during the course of treatment (final height prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the treating pediatrician together with the legal guardian and, if appropriate, the treated child. The bone age should be monitored during treatment with 6-12 months intervals.
In girls with bone maturation of older than 12 years and boys with maturation of older than 13 years, discontinuation of treatment should be considered taking into account the clinical parameters.
In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, medical advise should be sought.
NOTE: The administration interval should be 30±2 days in order to prevent the recurrence of precocious puberty.
11.25 mg: 3-Month 11.25 mg is to be given ONCE EVERY THREE MONTHS.
Incorporated in a depot formulation, the lyophilized microspheres are to be reconstituted and administered as a single intramuscular/subcutaneous injection, in accordance with the following directions: 1. Using a syringe with a 23 gauge needle, withdraw 2 mL of diluent from the ampule, and inject it into the vial.
2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.
3. Withdraw the entire contents of the vial into the syringe and inject it at the time of reconstitution.
The suspension settles very quickly following reconstitutions, therefore, it is preferable that Luprolex to be mixed and used immediately. Reshake suspension if settling occurs.
Although the potency of the reconstituted suspension has been shown to be stable for 24-hours, since the product does not contain a preservative, the suspension should be discarded if not used immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
Pediatric Population: Leuprorelin (Luprolex) must be administered under the supervision of a physician.
Leuprorelin (Luprolex) 11.25 mg for 3-month administration should be administered once every three (3) months (12 weeks) as a single intramuscular injection. Regardless of the dose chosen, the goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, other available GnRH agonists indicated for the treatment of CPP should be considered.
Leuprorelin (Luprolex) 11.25 mg for 3-month administration strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.
Leuprorelin (Luprolex) 11.25 mg for 3-month administration treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.
Overdosage
In early clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
3.75 mg: In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence that there is a clinical counterpart of this phenomenon.
11.25 mg: In rats, subcutaneous administration of leuprolide acetate as a single dose 225 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon.
Contraindications
Hypersensitiity to GnRH, GnRH agonist analogs or any of the excipients in Leuprorelin (Luprolex). Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature.
Undiagnosed abnormal vaginal bleeding.
Use in Pregnancy: Leuprorelin (Luprolex) is contraindicated in women who are or may become pregnant while receiving the drug. Leuprorelin (Luprolex) may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of Leuprorelin (Luprolex) throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by the drug, if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Use in Lactation: It is not known whether Leuprorelin (Luprolex) is excreted in human milk. Because many drugs are excreted in human milk, and because of the effects of Leuprorelin (Luprolex) on lactation and/or the breast-fed child have not been determined, Leuprorelin (Luprolex) should not be used by nursing mothers.
Use in Elderly: This product has not been studied in women over 65 years of age and is not indicated in this population.
3.75 mg: In girls with central precocious puberty: Pregnancy with lactation; undiagnosed vaginal bleeding.
11.25 mg: Norethindrone acetate is contraindicated in women with the following conditions: Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these conditions; Markedly impaired liver function or liver disease; Known or suspected carcinoma of the breast.
Warnings
1.88 mg: As the effects of Luprolex are present throughout the course of therapy, the drug should only be used in patients who require hormonal suppression for at least one month.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
When used at the recommended dose and dosing interval, Luprolex usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking Luprolex. Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus. (See Contraindications).
Since a decrease in bone mass may occur, the recommended duration of administration of this drug should be limited to 6 months. However, when necessary, the treatment period can be extended to 12 months, if norethindrone acetate 5 mg daily is given concurrently with Luprolex under careful observation of bone mass (for uterine myoma/fibroid, endometriosis).
3.75 mg: Safe use of leuprorelin acetate or norethindrone acetate in pregnancy has not been established clinically. Before starting treatment with Leuprorelin (Luprolex), pregnancy must be excluded.
When used as monthly at the recommended dose, Leuprorelin acetate (Luprolex) usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking Leuprorelin acetate (Luprolex). Therefore, patients should use non-hormonal methods of contraception.
Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with Leuprorelin acetate (Luprolex) and norethindrone acetate: Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking progestogens, the physician should be alert to the earliest manifestations of the disease in women taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be used with caution in women with risk factors, including lipid abnormalities or cigarette smoking.
Since a decrease in bone mass may occur, the recommended duration of administration of this drug should be limited to 6 months. However, when necessary, the treatment period can be extended to 12 months, if norethindrone acetate 5mg daily is given concurrently with Leuprorelin acetate (Luprolex) under careful observation of bone mass (for uterine myoma/fibroid, endometriosis).
11.25 mg: As the effects of Leuprorelin (Luprolex) are present throughout the course of therapy, the drug should only be used in patients who require hormonal suppression for at least three months. During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
When used at the recommended dose and dosing interval, Leuprorelin (Luprolex) usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking Leuprorelin (Luprolex). Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus. (See Contraindications).
Experience with Leuprorelin (Luprolex) 11.25mg in females has been limited to six months; therefore, exposure should be limited to six months of therapy.
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established clinically. Before starting treatment with Leuprorelin (Luprolex) pregnancy must be excluded. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with Leuprorelin (Luprolex) and norethindrone acetate: Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision or if there is sudden proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking progestogens, the physician should be alert to the earliest manifestations of the disease in women taking norethindron acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to initiation of add-back therapy with norethindron acetate. Norethindrone acetate should be used with caution in women with risk factors, including lipid abnormalities or cigarette smoking.
Since a decrease in bone mass may occur, the recommended duration of administration of this drug should be limited to 6 months. However, when necessary, the treatment period can be extended to 12 months, if norenthindrone acetate 5mg daily is given concurrently with Luprolex under careful observation of bone mass (for uterine myoma/fibroid, endometriosis).
Special Precautions
Patients should be aware of the following information: Since menstruation usually stops with effective doses of Leuprorelin (Luprolex), the patient should notify her physician if regular menstruation persists. Patients missing successive doses of Leuprorelin (Luprolex) may experience breakthrough bleeding.
Patients should not use Leuprorelin (Luprolex), if they are pregnant, breastfeeding, have undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in Leuprorelin (Luprolex).
A decrease in bone mass may occur owing to estrogen-reducing effect of Leuprorelin (Luprolex). Therefore, when it is necessary to administer the drug for a long period or to resume its administration, the drug should be cautiously be administered after the bone mass is examined as far as possible.
Patients should be counseled on the possibility of the development or worsening of depression and the occurrence of memory disorders.
It should be noted that the treatment of uterine myoma with Leuprorelin (Luprolex), is not a radical treatment. Therefore, as a rule, this drug should be used as a means of providing conservative treatment until operation on patients requiring operation or providing premenopausal conservative treatment. (See Warnings).
The effectiveness and safety in using Leuprorelin (Luprolex) for postoperative supplementary treatment has not been established. Therefore, it should not be used for prevention of relapse after curative operation (Premenopausal Breast Cancer).
Leuprorelin (Luprolex) does not exhibit antitumor effect or when any progression of the tumor is observed, the administration should be discontinued (Premenopausal Breast Cancer).
Elevation of serum testosterone due to the stimulating effect of Leuprorelin (Luprolex) as a highly active LH-RH derivative on the pituitary-gonad system may transiently aggravate bone pain in the early period after the first administration of the drug. If such a symptom occurs, pertinent symptomatic treatment should be given. Since urethral obstruction or spinal cord compression may occur, the drug should be cautiously administered, and close observation should be made during the first month after initiation of treatment and appropriate measures taken (Prostate Cancer).
Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.
Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
Leuprorelin (Luprolex) is contraindicated for use during pregnancy. Therefore, a non-hormonal method of contraception should be used during treatment. Patients should be advised that if they miss successive doses of Leuprorelin (Luprolex), breakthrough bleeding or ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.
Adverse events occurring in clinical studies with Leuprorelin (Luprolex) that are associated with hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne, myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was discontinued.
Patients should be counseled on the possibility of the development or worsening of depression and the occurrence of memory disorders.
The induced hypoestrogenic state also results in a loss in bone density over the course of treatment, some of which may not be reversible. Clinical studies show that concurrent hormonal therapy with norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with Leuprorelin (Luprolex).
(All patients received calcium supplementation with 1000 mg elemental calcium.)
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of Leuprorelin (Luprolex) and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one six-month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. Retreatment with Leuprorelin (Luprolex) alone is not recommended.
In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, Leuprorelin (Luprolex) therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with Leuprorelin (Luprolex) alone is instituted, and concomitant treatment with norethindrone acetate 5 mg daily should be considered. Retreatment with gonadotropin-releasing hormone analogs, including Leuprorelin (Luprolex) is not advisable in patients with major risk factors for loss of bone mineral content.
Because norethindrone acetate may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunctions require careful observation during norethindrone acetate add-back therapy.
Patients who have a history of depression should be carefully observed during treatment with norethindrone acetate and norethindrone acetate should be discontinued if severe depression occurs.
Convulsions: There have been postmarketing reports of convulsions in patients on Leuprorelin acetate therapy.
These included patients with and without concurrent medications and comorbid conditions. These include patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned previously.
The safety of Luprolex in prematures, newborns, and nursing infants has not been established.
1.88 mg: Careful Administration: For central Precocious Puberty: Usually a dose of 30 μg/kg of Leuprorelin is subcutaneously administered ONCE A MONTH depending upon the patient condition, the dosage may be increased up to 90 μg/kg.
For uterine myoma/fibroids/endometriosis: 1.88mg preparation may be used for patients with weight less than 50 kg. However, the patients with heavy weight or markedly large uterus, 3.75 mg is administered.
3.75 mg: In girls with central precocious puberty: Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary.
The therapy is a long-term treatment, adjusted individually. Leuprorelin (Luprolex) should be administered as precisely as possible in regular monthly periods. An exceptional delay of the injection date for a few days (30±2 days) does not influence the results of the therapy.
In the event of a sterile abscess at the injection site (mostly reported after I.M. Injection of higher than the recommended dosage) the absorption of leuprorelin acetate from the depot can be decreased. In this case the hormonal parameters (testosterone, estradiol) should be monitored at 2-week intervals.
The treatment of children with progressive brain tumors should follow a careful individual appraisal of the risks and benefits. The occurrence of vaginal bleeding, spotting and discharge after the first injection may occur as a sign of hormone withdrawal in girls. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.
Bone mineral density (BMD) may decrease during GnRH therapy for central precocious puberty. However, after cessation of treatment subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.
Slipped femoral epiphysis can be seen after withdrawal of GnRH treatment. The suggested theory is that the low concentration of estrogen during treatment with GnRH agonists weakens the epiphysial plate.
The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.
11.25 mg: Monitoring and Laboratory Tests: Response to Leuprorelin (Luprolex) 11.25 mg for 1-month administration should be monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels beginning 1-2 months following initiation of therapy, with changing doses, or potentially during therapy in order to confirm maintenance of efficacy. Measurement of bone age for advancement should be done every 6-12 months.
Response to Leuprorelin (Luprolex) 11.25 mg for 3-month administration should be monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels at months 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. Additionally, height (for calculation of growth rate) and bone age should be assessed every 6-12 months.
Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels. Gonadotropins and/or sex steroids may increase or rise above prepubertal levels if the dose is inadequate. Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels.
Adverse Reactions
Postmarketing: The following adverse reactions have been identified during post-approval use of Leuprorelin (Luprolex). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with Leuprorelin (Luprolex).
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg. joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Other events reported are: Hepato-biliary disorder: Rarely reported serious liver injury.
Injury, poisoning and procedural complications: Spinal fracture.
Investigations: Decreased WBC.
Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms.
Nervous System Disorder: Convulsions, peripheral neuropathy, paralysis.
Vascular Disorder: Hypotension.
Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke and transient ischemic attack.
Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.
Pituitary Apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status and sometimes, cardiovascular collapse. Immediate medical attention has been required.
General: Endometriosis, Uterine myoma/fibroids, Premenopausal Breast Cancer: Hypoestrogenism-related symptoms, Skin & appendages disorder: Hair loss.
Musculo-skeletal system disorder: Arthralgia, myalgia.
Central & peripheral nervous system disorders: Headache, Dizziness and Paresthesia.
Autonomic nervous system disorder: Increased sweating.
Vision disorder: Visual disturbance.
Psychiatric disorders: Decreased libido, emotional lability, depressions and sleep disorders.
Reproductive disorders, Female: Breast size decrease, dry vagina/vaginitis.
Body as a whole-General disorders: Hot flushes, edema and weight changes.
Hypersensitivity: Anaphylactic reaction, rash and pruritus.
Gastrointestinal: Nausea, Vomiting and Anorexia.
Liver: Abnormal liver function test values, usually transient.
Administration site: Injection site reactions.
Endometriosis, Uterine myoma/fibroids: Cardiovascular: Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.
Prostate Cancer: Flare phenomenon: Bone pain, urinary tract obstruction and hematuria (as urinary symptoms), Weakness of lower extremity/paresthesia (as neurologic symptoms).
Hypersensitivity: Anaphylactic reaction, rash and pruritus.
Endocrine: Hot flushes, diaphoresis, decreased libido, impotence, orchiatrophy and gynecomastia.
Gastrointestinal: Nausea, vomiting, anorexia and diarrhea.
Musculo-skeletal system disorder: Decreased bone mass.
Liver: Abnormal liver function test values, usually transient.
Administration site: Injection site reaction.
Others: Headache, edema, dizziness and depression.
1.88 mg: Central Precocious Puberty: Administration site: Injection site reactions.
3.75 mg: Central Precocious Puberty: In children: In the initial phase of therapy, a short-term increase as flare-up of the sex hormone level occurs, followed by a decrease to values within the pre-pubertal range. Due to pharmacological effect, adverse events may occur particularly at the beginning of treatment.
Immune system disorders: general allergic reactions (fever, rash, e.g. itching, anaphylactic reactions).
Psychiatric disorders: emotional lability
Nervous system disorders: headache, pituitary haemorrhage following initial administration in patients with pituitary adenoma, seizure.
Gastrointestinal disorders: abdominal pain/abdominal cramps, nausea/vomiting.
Skin and subcutaneous tissue disorders: acne.
Reproductive system and breast disorders: vaginal bleeding, spotting, discharge.
General disorders and administration site conditions: injection site reactions.
Note: In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of treatment) should be assessed as a sign of potential underdosage. The pituitary suppression should then be determined by an LHRH test.
11.25 mg: Central Precocious Puberty: The most common adverse reactions with GnRH agonists are injection site reactions/pain including abscess, general pain, headache, emotional lability and hot flushes/sweating.
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug (hormonal flare effect). Therefore, an increase in clinical signs and symptoms of puberty may be observed. [See Warnings and Precautions]
The following adverse events have been observed with this or other formulations of leuprolide acetate injection. As leuprolide has multiple indications, and therefore patient populations, some of these adverse events may not be applicable to every patient.
Allergic reactions (anaphylactic, rash, urticarial, and photosensitivity reactions) have also been reported.
Gastrointestinal Disorders: nausea, abdominal pain, vomiting.
General Disorders and Administration Site Conditions: chest pain, injection site reactions including induration and abscess have been reported.
Investigations: decreased WBC, weight increased.
Metabolism and Nutrition Disorders: diabetes mellitus.
Musculoskeletal and Connective Tissue Disorders: tenosynovitis-like symptoms.
Nervous System Disorders: neuropathy peripheral, convulsion, spinal fracture/paralysis.
Skin and Subcutaneous Tissue Disorders: hot flush, flushing, hyperhidrosis.
Reproductive System and Breast Disorders: prostate pain.
Vascular Disorders: hypertension, hypotension.
Drug Interactions
11.25 mg: No pharmacokinetic-based drug-drug interaction studies have been conducted with Leuprorelin (Luprolex). However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.
Drug/Laboratory Test Interactions: Administration of Leuprorelin (Luprolex) in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of Leuprorelin (Luprolex) may be misleading.
Storage
Store at a room temperature not exceeding 25°C and avoiding heat. Protect from freezing.
ATC Classification
L02AE02 - leuprorelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.
Presentation/Packing
Powd for inj [vial + amp (diluent)] 1.88 mg x 1's. 3.75 mg x 1's. 11.25 mg x 1's.
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