Leuprolide Acetate
2.8 mL Injection

What the medication is used for:

 LEUPROLIDE is used in the palliative treatment of prostate cancer. Palliative treatment is the relief of symptoms associated with a disease; it is not a cure.

Leuprolide acetate is chemically similar to gonadotropin-releasing hormone (GnRH or LHRH); a hormone which occurs naturally in your body. Normally, your body releases small amounts of LHRH and this leads to events which stimulate the production of sex hormones. However, when you inject Leuprolide , the normal events that lead to sex hormone production are interrupted and testosterone is no longer produced by the testes. Decreasing the levels of testosterone leads to decreased symptoms associated with prostate cancer.

When it should not be used:

• if you are allergic to leuprolide acetate, any similar nonapeptides (e.g., histrelin, desorelin), or any of the non-medicinal ingredients in LEUPROLIDE
• in women who are or may become pregnant
• in women who are breast-feeding

What the medicinal ingredient is:

What the non-medicinal ingredients are:
Each 2.8 mL multiple-dose vial contains benzyl alcohol, sodium chloride, and sterile water for injection. Each vial also contains sodium hydroxide and/or acetic acid.

What dosage forms it comes in:
LEUPROLIDE is a drug which contains 5 mg of leuprolide acetate per mL. It comes in 2.8 mL multiple-dose vials. LEUPROLIDE is supplied as a 14-day kit.

WARNINGS AND PRECAUTIONS

• LEUPROLIDE should be prescribed by a doctor experienced with this type of drug.

• worsening of symptoms of prostate cancer at the beginning of the treatment  bone thinning (osteoporosis)

• You are allergic to any component of the medication.

You have previous history of obstructive uropathy (difficulty urinating due to a block in the urinary tract).

You have family history of osteoporosis or are a chronic user of drugs that can reduce bone mass such as anticonvulsants, corticosteroids, alcohol and/or tobacco. LEUPROLIDE can cause thinning of the bone and may pose additional risk in patients with such a history.

You have had or are suspected of having seizures, epilepsy, cerebrovascular disorder, central nervous system anomalies, or brain tumor.

You are taking other medication(s) that have been associated with convulsions or seizures such as bupropion and any selective serotonin reuptake inhibitor (SSRI) medication for depression.

You have a history of heart disease or disorders, or have a genetic heart condition called “long QT syndrome”.

You have high blood sugar (diabetes). LEUPROLIDE may affect your blood sugar and you may need to test your blood sugar more frequently while receiving treatment with LUPRON®.

You have low red blood cell counts. LEUPROLIDE may cause a decrease in red blood cells (anemia).

During the first few weeks of treatment with Leuprolide , you may experience worsening of symptoms or onset of new symptoms; including bone pain, presence of blood in the urine or difficulty urinating.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor and pharmacist if you are taking, have been taking, or are planning to take any other medicines, including nonprescription drugs (such as drug products for colds or nausea).

In particular, if you take the following medicines:

• medicines used to correct heart rhythm such as quinidine, disopyramide, amiodarone, dronedarone, sotalol, dofetilide, ibutilide, flecainide
• propafenone
• medicines used to treat schizophrenia such as chlorpromazine
• medicines to treat depression such as amitriptyline, nortriptyline
• certain antibiotics and antimicrobials such as erythromycin, clarithromycin, azithromycin, moxifloxacin
• antimalarials (e.g., quinine)
• antifungals
• medicines used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy and surgery such as ondansetron
• medicines used for the relief of bronchospasm in conditions like asthma and chronic obstructive pulmonary disease such as salbutamol

PROPER USE OF THIS MEDICATION

The recommended dose of LEUPROLIDE is 1 mg (0.2 mL), as a single daily subcutaneous injection.
Only a small amount of LEUPROLIDE is needed once a day. Use the recommended ½ cc presterilized disposable syringe (see Instructions for Use Leaflet). Syringes are provided in the Patient Administration Kit.

Change the site of injection as instructed by your doctor.
As a guide, the usual sites of injection are indicated below:
SUGGESTED ROTATION OF THE INJECTION SITE

In case of overdose, contact a healthcare practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

Follow these instructions unless instructed otherwise by your doctor: if you miss an injection at the usual time, take it as soon as you remember, if you remember on the same day. If not, do not take the missed dose at all. Simply wait until it is time for your next dose. Do not take two doses at once.

Do not stop your daily injections because you feel better. You need one injection a day to make sure LEUPROLIDE keeps working for you.

It is very important that your doctor check your progress at regular medical visits.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Postmarketing reports of convulsions have been observed in patients taking Leuprolide , These included patients in the female and pediatric populations, patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, 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 conditions mentioned above.

In the first few weeks of taking Leuprolide , your testosterone levels will initially increase and then decline over several weeks. During this period some patients may experience worsening of urinary symptoms and/or a temporary increase in bone pain. Should this occur, contact your doctor immediately.

The following side effects are commonly experienced after the initial rise and occur due to decreasing levels of testosterone in the body:

• general pain or flu-like symptoms
• hot flashes/sweats
• joint and muscle pain
• emotional changes such as feeling depressed

worsening urinary symptoms

Should these side effects persist or if they are severe, contact your doctor immediately.
Notify your doctor if you develop new or worsened symptoms of depression after beginning LEUPROLIDE treatment
A local skin reaction may occur: itching, redness, burning, and/or swelling at the injection site. These reactions usually are mild and disappear after a few days. If they persist or worsen, tell your doctor.

HOW TO STORE IT

Store LEUPROLIDE vials or kits in the refrigerator (2 to 8°C) and protect from light (keep in carton until use).

As with other medications, KEEP OUT OF REACH OF CHILDREN.

Leuprolide Acetate
2.8 mL Injection

DESCRIPTION

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5- oxo -L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:

Leuprolide acetate injection is a sterile, aqueous solution intended for daily subcutaneous injection. It is available in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. The pH range is 4.0 to 6.0.

CLINICAL PHARMACOLOGY

Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

Leuprolide acetate is not active when given orally.

A pharmacokinetic study of leuprolide acetate in children has not been performed.

In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration.

Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.

Metabolism
In healthy adult male volunteers, a 1 mg bolus of leuprolide 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.

Excretion
Following administration of leuprolide acetate depot 3.75 mg to three adult 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 has not been determined.

Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

CLINICAL STUDIES

In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate.

The following physiologic effects have been noted with the chronic administration of leuprolide acetate in this patient population.

• Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal plates will not close prematurely.
• Organ Growth. Reproductive organs will return to a prepubertal state.
• Menses. Menses, if present, will cease.

INDICATIONS AND USAGE

Leuprolide acetate injection is indicated in the treatment of children with central precocious puberty. Children should be selected using the following criteria:

• Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual characteristics earlier than 8 years in females and 9 years in males.
• Clinical diagnosis should be confirmed prior to initiation of therapy:
  • Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The sensitivity and methodology of this assay must be understood.
  • Bone age advanced 1 year beyond the chronological age.

• Baseline evaluation should also include:
  • Height and weight measurements.
  • Sex steroid levels.
  • Adrenal steroid level to exclude congenital adrenal hyperplasia.
  • Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor.
  • Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor.
  • Computerized tomography of the head to rule out intracranial tumor.

CONTRAINDICATIONS

• Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in leuprolide acetate injection. Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature.1,2
• Leuprolide acetate is contraindicated in women who are or may become pregnant while receiving the drug. Leuprolide acetate may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate 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 this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of leuprolide acetate, the patient should be apprised of the potential hazard to the fetus.

WARNINGS

Initially, leuprolide acetate, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of leuprolide acetate treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with leuprolide acetate, pregnancy must be excluded. Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

PRECAUTIONS

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. Patients with known allergies to benzyl alcohol, an ingredient of the drug’s vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site.

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.

See INFORMATION FOR PATIENTS which appears after the REFERENCE section.

Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and prostate-specific antigen (PSA). In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Castrate levels were reached within two to four weeks and once attained were maintained for as long as drug administration continued.

See CLINICAL PHARMACOLOGY: Pharmacokinetics section.

Drug/Laboratory Test Interactions
Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued.

Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults (≥18 years) with leuprolide acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. However, no clinical studies have been conducted with leuprolide acetate to assess the reversibility of fertility suppression.

Teratogenic Effects
Pregnancy Category X
(See CONTRAINDICATIONS and WARNINGS sections.) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, leuprolide acetate produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations throughout gestation. There was increased fetal mortality and decreased fetal weights with the two higher doses of leuprolide acetate in rabbits and with the highest dose in rats. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug.

It is not known whether leuprolide acetate is excreted in human milk. Leuprolide acetate should not be used by nursing mothers.

See labeling For Pediatric Use Leuprolide Acetate Injectionfor the safety and effectiveness in children with central precocious puberty.

In the clinical trials for leuprolide acetate injection, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy, and safety of leuprolide acetate in this population.

ADVERSE REACTIONS

In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain. In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction. In a comparative trial of leuprolide acetate injection versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded.

In this same study, the following adverse reactions were reported in less than 5% of the patients on leuprolide acetate.

Cardiovascular System
–Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli;

Gastrointestinal System
–Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal disturbance, Peptic ulcer, Rectal polyps;

Endocrine System
–Libido decrease, Thyroid enlargement;

Musculoskeletal System
–Joint pain;

Central/Peripheral Nervous System
–Anxiety, Blurred vision, Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral neuropathy, Syncope/blackouts, Taste disorders;

Respiratory System
–Cough, Pleural rub, Pneumonia, Pulmonary fibrosis;

Integumentary System
–Carcinoma of skin/ear, Dry skin, Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions;

Urogenital System
–Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction;

Miscellaneous
–Depression, Diabetes, Fatigue, Fever/chills, Hypoglycemia, Increased BUN, Increased calcium, Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone).

In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving leuprolide acetate.

Cardiovascular System
–Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing (eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack;

Gastrointestinal System
–Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam), Rectal fistula/erythema;

Endocrine System
–Libido increase, Thyroid nodule;

Musculoskeletal System
–Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness, Muscle tenderness, Pelvic fibrosis, Spasms/cramps;

Central/Peripheral Nervous System
–Auditory hallucinations/tinnitus, Decreased hearing, Decreased reflexes, Euphoria, Hyperreflexia, Loss of smell, Motor deficiency;

Respiratory System
–Chest tightness, Decreased breathing sounds, Hemoptysis, Pleuritic chest pain, Pulmonary infiltrate, Rales/rhonchi, Rhinitis, Strep throat, Wheezing/bronchitis;

Integumentary System
–Boil (pubic), Bruises, Hives, Keratosis, Mole, Shingles, Spiders;

Urogenital System
–Blisters on penis, Inguinal hernia, Penile swelling, Post void residual, Prostatic pain, Pyuria;

Miscellaneous
–Abdominal distention, Facial swelling/edema, Feet burning, Flu, Eyelid growth, Hypoproteinemia, Accidental injury, Knee effusion, Mass, Pallid, Sallow, Weakness.

During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) 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 (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively.

Cardiovascular System
– Hypotension; Myocardial infarction;

Endocrine System
– Diabetes;

Gastrointestinal System
– Hepatic dysfunction;

Hemic and Lymphatic System
– Decreased WBC;

Integumentary System
– Hair growth;

Central/Peripheral Nervous System
– Convulsion, Spinal fracture/paralysis, Hearing disorder;

Miscellaneous
– Hard nodule in throat, Weight gain, Increased uric acid;

Musculoskeletal System
– Tenosynovitis-like symptoms;

Respiratory System
– Respiratory disorders.

Changes in Bone Density
Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density.

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.

See other leuprolide acetate for depot suspension and leuprolide acetate injection package inserts for other events reported in the same and different patient populations.

OVERDOSAGE

In rats, subcutaneous administration of 125 to 250 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. In early clinical trials using leuprolide acetate in adult patients, 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.

DOSAGE AND ADMINISTRATION

Leuprolide acetate injection can be administered by a patient/parent or health care professional.

The dose of leuprolide acetate injection must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.

After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6-12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters.

The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy.

As with other drugs administered by injection, the injection site should be varied periodically.

Discontinuation of leuprolide acetate injection should be considered before age 11 for females and age 12 for males.

The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose will be considered the maintenance dose.

Follow the pictorial directions on the reverse side of this package insert for administration.

NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter before each use.

HOW SUPPLIED

Leuprolide acetate injection is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows:

• 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs.
• Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use.

REFERENCES

• Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct; 161(3): 455.
• Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. ObstetGynecol 1991 Nov; 78: 943–946.