Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/9
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Lupron Depot (Injection, Powder, Lyophilized, For Suspension)
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LUPRON DEPOT Must Be Administered Under The Supervision
Of A Physician.<br/>Endometriosis: The recommended
duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination
with norethindrone acetate is six months. The choice of LUPRON DEPOT
alone or LUPRON DEPOT plus norethindrone acetate therapy for initial
management of the symptoms and signs of endometriosis should be made
by the health care professional in consultation with the patient and
should take into consideration the risks and benefits of the addition
of norethindrone to LUPRON DEPOT alone. If the symptoms of endometriosis recur after a course of therapy,
retreatment with a six-month course of LUPRON DEPOT monthly 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. LUPRON DEPOT alone isnot recommended for
retreatment. If norethindrone acetate is contraindicated for the individual
patient, then retreatment is not recommended. An assessment of cardiovascular risk and management of risk factors
such as cigarette smoking is recommended before beginning treatment
with LUPRON DEPOT and norethindrone acetate.<br/>Uterine Leiomyomata (Fibroids): Recommended duration of therapy with LUPRON DEPOT
3.75 mg is up to 3 months. The
symptoms associated with uterine leiomyomata will recur following
discontinuation of therapy. If additional treatment with LUPRON DEPOT
3.75 mg is contemplated, bone density should be assessed prior to
initiation of therapy to ensure that values are within normal limits. The recommended dose of LUPRON DEPOT is
3.75 mg, incorporated in a depot formulation. The lyophilized microspheres
are to be reconstituted and administered monthly as a single intramuscular
injection. For optimal performance of
the prefilled dual chamber syringe (PDS), read and follow the following
instructions: 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.
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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: LUPRON DEPOT is available
in a prefilled dual-chamber syringe containing sterile lyophilized
microspheres which, when mixed with diluent, become a suspension intended
as a monthly intramuscular injection. The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber
syringe contains leuprolide acetate (3.75 mg), purified gelatin (0.65
mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol
(6.6 mg). The second chamber of diluent contains carboxymethylcellulose
sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for
injection, USP, and glacial acetic acid, USP to control pH. During the manufacture of LUPRON
DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
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Leuprolide acetate is a
long-acting GnRH analog. A single monthly injection of LUPRON DEPOT
3.75 mg 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. Leuprolide
acetate is not active when given orally. Intramuscular injection of
the depot formulation provides plasma concentrations of leuprolide
over a period of one month.<br/>Pharmacokinetics:<br/>Absorption: A single
dose of LUPRON DEPOT 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 0.30 ng/mL.<br/>Distribution: The mean
steady-state volume of distribution of leuprolide following intravenous
bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins
ranged from 43% to 49%.<br/>Metabolism: In healthy
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 ofC-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.<br/>Excretion: Following
administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5%
of the dose was recovered as parent and M-I metabolite in the urine.<br/>Special Populations: The pharmacokinetics
of the drug in hepatically and renally impaired patients have not
been determined.<br/>Drug Interactions: No pharmacokinetic-based
drug-drug interaction studies have been conducted with LUPRON DEPOT.
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.
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Each LUPRON DEPOT 3.75 mg
kit (NDC 0074-3641-03) contains: Each syringe contains sterile
lyophilized microspheres, which is leuprolide incorporated in a biodegradable
copolymer of lactic and glycolic acids. When mixed with diluent, LUPRON
DEPOT 3.75 mg is administered as a single monthly IM injection. Store at 25��C (77��F);
excursions permitted to 15-30��C (59-86��F) [See USP Controlled
Room Temperature]
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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. 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.
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leuprolide acetate
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Lupron Depot (Injection, Powder, Lyophilized, For Suspension)
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Clinical Trials: Estradiol levels
may increase during the first weeks following the initial injection
of LUPRON, but then decline to menopausal levels. This transient increase
in estradiol can be associated with a temporary worsening of signs
and symptoms . As would be expected with a drug that lowers serum estradiol levels,
the most frequently reported adverse reactions were those related
to hypoestrogenism. The monthly formulation of LUPRON DEPOT
3.75 mg was utilized in controlled clinical trials that
studied the drug in 166 endometriosis and 166 uterine fibroids patients.
Adverse events reported in���5% of patients in either of these
populations and thought to be potentially related to drug are noted
in the following table. In one controlled
clinical trial utilizing the monthly formulation of LUPRON DEPOT,
patients diagnosed with uterine fibroids received a higher dose (7.5
mg) of LUPRON DEPOT. Events seen with this dose that were thought
to be potentially related to drug and were not seen at the lower dose
included glossitis, hypesthesia, lactation, pyelonephritis, and urinarydisorders. Generally, a higher incidence of hypoestrogenic effects
was observed at the higher dose. Table 3 lists the potentially drug-related adverse events observed
in at least 5% of patients in any treatment group during the first
6 months of treatment in the add-back clinical studies. In the controlled clinical
trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%)
patients in the LD/N group reported experiencing hot flashes on one
or more occasions during treatment. During Month 6 of treatment, 32
of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in
the LD/N group reported having experienced hot flashes. The mean number
of days on which hot flashes were reported during this month of treatment
was 19 and 7 in the LD and LD/N treatment groups, respectively. The
mean maximum number of hot flashes in a day during this month of treatment
was 5.8 and 1.9 in the LD and LD/N treatment groups, respectively.<br/>Changes in Bone Density: In controlled
clinical studies, patients with endometriosis (six months of therapy)
or uterine fibroids (three months of therapy) were treated with LUPRON
DEPOT 3.75 mg. In endometriosis patients, vertebral bone density as
measured by dual energy x-ray absorptiometry (DEXA) decreased by an
average of 3.2% at six months compared with the pretreatment value.
Clinical studies demonstrate that concurrent hormonal therapy (norethindrone
acetate 5 mg daily) and calcium supplementation is effective in significantly
reducing the loss of bone mineral density that occurs with LUPRON
treatment, without compromising the efficacy of LUPRON in relieving
symptoms of endometriosis. LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated
in two clinical trials. The results from this regimen were similar
in both studies. LUPRON DEPOT 3.75 mg was used as a control group
in one study. The bone mineral density data of the lumbar spine from
these two studies are presented in Table 4. When
LUPRON DEPOT 3.75 mg was administered for three months in uterine
fibroid patients, vertebral trabecular bone mineral density as assessed
by quantitative digital radiography (QDR) revealed a mean decrease
of 2.7% compared with baseline. Six months after discontinuation of
therapy, a trend toward recovery was observed. Use of LUPRON DEPOT
for longer than three months (uterine fibroids) or six months (endometriosis)
or in the presence of other known risk factors for decreased bone
mineral content may cause additional bone loss and is not recommended.<br/>Changes in Laboratory Values During Treatment:<br/>Postmarketing: 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 LUPRON. 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 disorder, gastrointestinal distress, and shortness
of breath) have been reported individually and collectively. Other
events reported are: Cardiovascular System���Hypotension, Pulmonary embolism; Hemic and Lymphatic System - Decreased
WBC; Central/Peripheral Nervous System - Convulsion, Peripheral neuropathy, Spinal fracture/paralysis; Musculoskeletal System - Tenosynovitis-like
symptoms; Urogenital System - Prostate pain.<br/>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 LUPRON
DEPOT and LUPRON Injection package inserts for other events reported
in different patient populations.
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Endometriosis: LUPRON DEPOT 3.75
mg is indicated for management of endometriosis, including pain relief
and reduction of endometriotic lesions. LUPRON DEPOT monthly with
norethindrone acetate 5 mg daily is also indicated for initial management
of endometriosis and for management of recurrence of symptoms. . Duration of initial treatment
or retreatment should be limited to 6 months.<br/>Uterine Leiomyomata (Fibroids): LUPRON DEPOT 3.75
mg concomitantly with iron therapy is indicated for the preoperative
hematologic improvement of patients with anemia caused by uterine
leiomyomata. The clinician may wish to consider a one-month trial
period on iron alone inasmuch as some of the patients will respond
to iron alone. (See Table 1.)
LUPRON may be added if the response to iron alone is considered inadequate.
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to three months. Experience with LUPRON DEPOT in females has been limited to women
18 years of age and older.
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Lupron Depot
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