LUPROLEX Leuprorelin Acetate 3.75mg Powder for IM/SC Injection 1's

Indications/Uses

Endometriosis, Uterine myoma/fibroids.
In children: Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age).
3.75 mg and 11.25 mg: Premenopausal breast cancer, Prostate cancer.

Dosage/Direction for Use

Leuprolin (Luprolex) Must Be Administered Under the Supervision of a Physician.
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) 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.
1.88 mg: Leuprorelin (Luprolex) 1.88 mg is to be given ONCE A MONTH.
For Uterine fibroids/endometriosis: For patients weighing less than 50 kg, 1.88 mg is administered as single intramuscular or subcutaneous injection.
For patients weighing more than 50 kg, or with a markedly large uterus, 3.75 mg is administered (e.g. as Leuprorelin (Luprolex) 3.75 mg powder for injection).
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 ≥20kg: 3.75 mg is administered [e.g. as Leuprorelin (Luprolex) 3.75 mg powder for injection].
Children with a body weight <20kg: In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty: 2mL [1.88 mg Leuprorelin (Luprolex)] is administered once a month as a single subcutaneous injection.
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 advice should be sought.
NOTE: The administration interval should be 30± 2 days in order to prevent the recurrence of precocious puberty.
3.75 mg: Leuprorelin (Luprolex) 3.75 mg is to be given ONCE A MONTH.
Pediatric Population: The treatment of children with leuprorelin (Luprolex) 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 ≥20kg: 2mL (3.75 mg leuprorelin acetate) suspension of 44.1 mg sustained-release microcapsules in 2 mL vehicle solution are administered once a month as a single subcutaneous injection.
Children with a body weight <20kg: In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty: 1mL (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 advice should be sought.
NOTE: The administration interval should be 30± 2 days in order to prevent the recurrence of precocious puberty.
11.25 mg: Leuprorelin (Luprolex) 3-Month 11.25 mg is to be given ONCE EVERY THREE MONTHS.
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 >20kg: 2 mL [11.25 mg Leuprorelin (Luprolex)] suspension of 130.0 mg sustained-release microcapsules in 2 mL vehicle solution are administered every 3 months as a single subcutaneous injection.
Children with a body weight <20kg: In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty: 1 mL [5.625 mg Leuprorelin (Luprolex)] is administered every 3 months 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 3-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 (Luprolex) 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 advice should be sought.
NOTE: The administration interval should be 90±2 days in order to prevent the recurrence of precocious puberty.

Overdosage

In early clinical trials using daily subcutaneous Leuprorelin (Luprolex) 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.
In cases of overdosage, standard of care monitoring and management principles should be followed.
1.88 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.
3.75 mg and 11.25 mg: In rats, subcutaneous administration of Leuprorelin (Luprolex) as a single dose 225 times the recommended human pediatric dose or 250 to 500 times the recommended human adult 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.

Contraindications

Hypersensitivity 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 uterine/vaginal bleeding.
This product is not indicated in postmenopausal women and has not been studied in this population.
In girls with central precocious puberty: Pregnancy and lactation; Undiagnosed vaginal bleeding.
When considering add-back therapy with norethindrone acetate (see Warnings), refer also to Contraindications in the norethindrone acetate prescribing information.
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.

Warnings

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.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The safety of Leuprorelin (Luprolex) in prematures, newborns, and nursing infants has not been established.
The following applies to Females: Leuprorelin (Luprolex) is contraindicated for use during pregnancy. Safe use of leuprorelin [or norethindrone acetate (see as follows)] in pregnancy has not been established clinically. Before starting treatment with leuprorelin acetate (Luprolex) pregnancy must be excluded.
When used at the recommended dose and dosing interval, Leuprorelin (Luprolex) usually inhibits ovulation and stops menstruation. Contraception is not ensured, 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).
The following applies to co-treatment with Leuprorelin (Luprolex) and norethindrone acetate in the treatment of Endometriosis: 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 Leuprorelin (Luprolex) ('add-back therapy') under careful observation of bone mass.
When considering add-back therapy with norethindrone acetate, refer also to Warnings and Precautions in the norethindrone acetate prescribing information.
The following applies to treatment of Uterine fibroids: Since a decrease in bone mass may occur, the recommended duration of administration of this drug should be limited to 6 months.
1.88 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 one month.
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.
Experience with Leuprorelin (Luprolex) 11.25 mg monotherapy in females has been limited to six months; therefore, monotherapy exposure should be limited to six months of therapy.

Special Precautions

Patients should be aware of the following information: Patients should be counselled on the possibility of the development or worsening of depression and the occurrence of memory disorders. In children, emotional lability, such as crying, irritability, impatience, anger and aggression has been reported.
Postmarketing reports of convulsions have been observed in patients on Leuprorelin (Luprolex) therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumours and in 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 (comorbid) conditions mentioned previously. Patients receiving a GnRH agonist who experience convulsion should be managed according to current clinical practice.
Patients should not use Leuprorelin (Luprolex) if they are allergic to any of the ingredients.
The following applies to Females: 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, or have undiagnosed abnormal vaginal bleeding.
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 a 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.
The following applies to Adult Females: 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 administered after the bone mass is examined as far as possible.
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.
The following applies to treatment of Endometriosis: 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 (all patients received calcium supplementation with 1000 mg elemental calcium).
In patients with major risk factors for decreased bone mineral content (see as previously mentioned), 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.
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.
Depression may occur or worsen during treatment with norethindrone acetate. Carefully observe women with a history of depression and consider discontinuing norethindrone acetate if depression recurs to a serious degree.
The following applies to treatment of Uterine fibroids: It should be noted that the treatment of uterine fibroids 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.
Retreatment with gonadotropin-releasing hormone analogs, including Leuprorelin (Luprolex) is not advisable in patients with major risk factors for loss of bone mineral content (see as previously mentioned).
In women with submucous fibroids there have been reports of severe bleeding following the administration of Leuprorelin (Luprolex) as a consequence of the acute degeneration of the fibroids. Patients should be warned of the possibility of abnormal bleeding or pain in case earlier surgical intervention is required.
Central precocious puberty: Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary.
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 (Luprolex) 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.
1.88 mg and 3.75 mg: 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.
11.25 mg: The therapy is a long-term treatment, adjusted individually. Leuprorelin (Luprolex) should be administered as precisely as possible in regular 3-monthly periods. An exceptional delay of the injection date for a few days (90±2 days) does not influence the results of the therapy.
3.75 mg and 11.25 mg: The following applies to treatment of Premenopausal Breast cancer: 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.
Leuprorelin (Luprolex) does not exhibit antitumor effect or when any progression of the tumor is observed, the administration should be discontinued.
The following applies to treatment of Prostate cancer: Initially, Leuprorelin (Luprolex), like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first weeks of treatment. Isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. A small number of patients may experience a temporary increase in bone pain. 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 in patients with metastatic vertebral lesions and/or with urinary tract obstruction.
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.
Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.

Use In Pregnancy & Lactation

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.
Nursing mothers: 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.

Adverse Reactions

Postmarketing: The following adverse reactions have been identified during post-approval use of leuprorelin. 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: Gastrointestinal Disorders: Abdominal pain.
General Disorders and Administration Site Conditions: Chest pain.
Respiratory, thoracic and mediastinal disorder: Interstitial lung disease.
Hepato-biliary disorder: Rarely reported serious liver injury.
Injury, poisoning and procedural complications: Spinal fracture.
Investigations: Decreased white blood cells (WBC), weight increased.
Metabolism and Nutrition Disorders: Diabetes mellitus.
Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms, severe muscle pain.
Nervous System Disorder: Convulsions, peripheral neuropathy, paralysis.
Reproductive System and Breast Disorders: Prostate pain (3.75 mg and 11.25 mg).
Vascular Disorder: Hypertension, 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 fibroids, Premenopausal Breast Cancer (3.75 mg and 11.25 mg): Hypoestrogenism-related symptoms: Skin & appendages disorder: Hair loss.
Musculo-skeletal system disorder: Arthralgia, myalgia, decreased bone mass.
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, depression 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.
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 (e.g. crying, irritability, impatience, anger, and aggression).
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.
3.75 mg and 11.25 mg: 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.
Cardiovascular: QT prolongation.

Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted with Leuprorelin (Luprolex). However, because leuprorelin 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.
3.75 mg and 11.25 mg: In males, since androgen deprivation treatment may prolong the QT interval, the concomitant use of Leuprorelin (Luprolex) with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as Class IA (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, should be carefully evaluated.

Caution For Usage

Special precautions for disposal and other handling: Always ensure the safety device to prevent needle-stick injury is deployed after injection. Any unused product or waste material should be disposed of in accordance with local requirements.

Storage

Store at a room temperature not exceeding 25°C and avoiding heat. Protect from freezing.

Action

Pharmacology: Mechanism of action: 1.88 mg and 3.75 mg: Repeated administration of either LH-RH in a massive dose or leuprorelin acetate, which is a highly potent LH-RH derivative, causes a transient pituitary - gonad system stimulating effect (acute effect) immediately after the first administration and then suppresses both the production and release of gonadotropin in the pituitary. It further suppresses the response of the ovary and testis to gonadotropin, resulting in a decrease in estradiol and testosterone producing action (chronic effect). The LH releasing activity of Leuprorelin Acetate is approximately equal to 100 times that of LH-RH, and its action of suppressing the pituitary-gonad function is stronger than that of LH-RH. Since Leuprorelin Acetate is a highly potent LH-RH derivative, its strong action of suppressing the pituitary-gonad function is attributed to its higher resistance to proteolytic enzymes and higher affinity for LH-RH receptors in comparison with LH-RH. Moreover, since Leuprorelin (Luprolex) is a sustained release preparation, it constantly releases Leuprorelin Acetate into the blood to effectively reduce the response of the ovary and testis, producing a highly favorable pituitary-gonad inhibitory action.
11.25 mg: Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy.
Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.
1.88 mg and 3.75 mg: Action on gonadotropic hormone suppression: In patients with endometriosis, uterine myoma or premenopausal breast cancer, subcutaneous injection of Leuprorelin Acetate once every 4 weeks generally causes serum estradiol to fall to a value near the menopausal level. Thus, this drug produces an ovarian function suppressing effect, with resultant inhibition of normal ovulation and cessation of menstruation.
In patients with prostate cancer, subcutaneous administration of Leuprorelin Acetate once every 4 weeks causes serum testosterone to fall below the castration level, indicating a pharmacological castrating effect.
In girl and boy patients with central precocious puberty, subcutaneous administration of leuprorelin acetate, once every 4 weeks, reduces the serum level of gonadotropic hormone to the prepubertal level, exhibiting an action of delaying the progression of secondary sex characteristics.
Pharmacodynamics: 11.25 mg: In humans, administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in concentrations of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased concentrations of LH and FSH. In males, testosterone is reduced to castrate concentrations. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years.
Leuprolide acetate is not active when given orally.
Pharmacokinetics: 1.88 mg: Endometriosis: Blood concentrations: Figure 1 shows blood concentration in a study in which 1.88 mg or 3.75 mg, as Leuprorelin (Luprolex), was administered subcutaneously to patients with endometriosis in a total of six times at 4-week intervals. When 3.75 mg, as Leuprorelin (Luprolex), was administered subcutaneously to patients with endometriosis (77 patients) six times at 4-week intervals, the combined blood concentration of the unchanged compound and metabolite M-I* revealed no accumulation.
*M - I: Tyr - D - Leu - Leu - Arg - Pro - NHC2H5. (See Figure 1.)

Urinary excretion: The following table shows the urinary excretion rates (%) of the unchanged compound and metabolite M-I at 24 hours after the first administration and 24 hours after the sixth administration, when 3.75 mg, as Leuprorelin (Luprolex), was administered subcutaneously to patients with endometriosis six times at 4-week intervals.
Uterine fibroids: The pharmacokinetics in patients with uterine myoma are considered to be the same as those in patients with endometriosis, which is the same estrogen dependent disease as uterine myoma and is occurring in nearly the same age group as uterine myoma.
Central precocious puberty: Blood concentrations: Figure 2 shows the blood concentrations of the unchanged compound after the first administration, when 30 μg/kg, as Leuprorelin (Luprolex), was given subcutaneously to patients with central precocious puberty twelve times at 4-week intervals. Judging from the trend of blood concentration of the unchanged compound, this drug is not considered to accumulate. (See Figure 2.)

Urinary excretion: When a single dose of 30 μg/kg, as Leuprorelin (Luprolex), was subcutaneously administered to patients with central precocious puberty (1 patient), the urinary excretion rates of the unchanged compound and its metabolite M-I up to 28 days after administration were 1.8% and 7.1%, respectively.
Absorption: 3.75 mg: 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 leuprorelin and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprorelin concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.
11.25 mg: Following a single injection of the three month formulation of Leuprorelin (Luprolex) 11.25 mg in female subjects, a mean plasma leuprorelin concentration of 36.3 ng/mL was observed at 4 hours. Leuprorelin 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) leuprorelin concentration from 3 to 12 weeks was 0.23 ± 0.09 ng/mL. However, intact leuprorelin 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: 3.75 mg and 11.25 mg: 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: 3.75 mg and 11.25 mg: In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously revealed that the mean systemic clearance was 7.6 L/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.
11.25 mg: In a pharmacokinetic/pharmacodynamics study of endometriosis patients, intramuscular Leuprorelin (Luprolex) 11.25 mg every 12 weeks or intramuscular Leuprorelin (Luprolex) 3.75 mg 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 leuprorelin concentrations.
Excretion: 3.75 mg and 11.25 mg: 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.

MedsGo Class

Trophic Hormones & Related Synthetic Drugs / Cancer Hormone Therapy