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FIRMAGON®
(degarelix) Injection
FIRMAGON is a sterile lyophilized powder for injection containing degarelix (as the acetate) and mannitol. Degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are Damino acids. The acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilization.
The chemical name of degarelix is D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-Dphenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L leucyl-N6–(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formula of C82H103N18O16Cl and a molecular weight of 1632.3 Da.
Degarelix has the following structural formula:
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FIRMAGON delivers degarelix acetate, equivalent to 120 mg of degarelix for the starting dose, and 80 mg of degarelix for the maintenance dose. The 80 mg vial contains 200 mg mannitol and the 120 mg vial contains 150 mg mannitol.
FIRMAGON is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer.
FIRMAGON is administered as a subcutaneous injection in the abdominal region only.
| Starting dose | Maintenance dose - Administration every 28 days |
| 240 mg given as two subcutaneous injections of 120 mg at a concentration of 40 mg/mL | 80 mg given as one subcutaneous injection at a concentration of 20 mg/mL |
The first maintenance dose should be given 28 days after the starting dose.
FIRMAGON® is to be administered by a healthcare professional only. Before administering FIRMAGON read the Instructions for reconstitution and administration carefully.
As with other drugs administered by subcutaneous injection, the injection site should vary periodically. Injections should be given in areas of the abdomen that will not be exposed to pressure, e.g., not close to waistband or belt nor close to the ribs.
FIRMAGON is supplied as a powder to be reconstituted with Sterile Water for Injection, USP (WFI). The instruction for reconstitution needs to be carefully followed. Administration of other concentrations is not recommended. Read the complete instructions before performing the injection.
NOTE: FIRMAGON is for subcutaneous administration to the abdominal region only.
Follow aseptic technique.
FIRMAGON 240 mg Starting Dose Kit contains:
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FIRMAGON 80 mg Maintenance Dose Kit contains:
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In addition the healthcare professional will need:
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The drug product must be prepared using the following instructions:
NOTE: The mixing process must be repeated for the two injections of the Starting Dose prior to injecting the product into the patient's abdomen.
Step 1: Attaching the vial adaptor to the vial
IMPORTANT: DO NOT USE if there is no powder in the vial or the Sterile Water, USP is discolored.
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IMPORTANT: Do not touch the top of the vial after wiping.
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IMPORTANT: Do not touch the vial adapter.
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Step 2: Assembling the syringe
IMPORTANT: Do not pull the back stopper (flange) (s) off the syringe.
NOTE: You will only feel light resistance screwing the plunger rod in position.
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Step 3: Transferring sterile water, USP from the syringe to the vial
IMPORTANT: Do not pull off the Luer lock adaptor (u).
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IMPORTANT: Be careful not to over twist the syringe.
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Step 4: Preparing the reconstituted injection
IMPORTANT:
NOTE: If the powder adheres to the side of the vial, tilt the vial slightly. A ring of small air bubbles on the surface of the liquid is acceptable.
Reconstitution time can take up to 15 min but usually takes a few minutes.
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Step 5: Transferring the liquid to the syringe
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Step 6: Preparing the syringe for injection
NOTE: Reconstitute just prior to administration.
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Step 7: Preparing the patient
IMPORTANT:
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Step 8: Performing the injection
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IMPORTANT: If blood appears in the syringe, the product should not be injected. Discontinue the injection and discard the syringe and the needle (reconstitute a new dose for the patient).
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IMPORTANT: Do not rub the injection site after retracting the needle.
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Step 9: Locking the needle into the shield
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IMPORTANT: Syringe is for single use only. Do not reuse the syringe and needle.
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Step 10: Advising the patient
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Disposing used needles and syringes
One starting dose comprises 240 mg given as two 3 mL injections of 120 mg each.
Powder for injection 120 mg:
One vial of FIRMAGON 120 mg contains 120 mg degarelix. Each vial is to be reconstituted with a prefilled syringe containing 3 mL of Sterile Water for Injection. 3 mL is withdrawn to deliver 120 mg degarelix at a concentration of 40 mg/mL.
One maintenance dose comprises 80 mg given as one 4 mL injection.
Powder for injection 80 mg:
One vial of FIRMAGON 80 mg contains 80 mg degarelix. Each vial is to be reconstituted with a prefilled syringe containing 4.2 mL of Sterile Water for Injection. 4 mL is withdrawn to deliver 80 mg degarelix at a concentration of 20 mg/mL.
FIRMAGON is available as:
NDC 55566-8403-1, Starting dose – One carton contains:
Two vials each with 120 mg powder for injection
Two prefilled syringes containing 3 mL of sterile water
for injection, USP
Two vial adapters
Two administration needles
NDC 55566-8303-1, Maintenance dose – One carton contains:
One vial with 80 mg powder for injection
One prefilled syringe containing 4.2 mL of sterile water
for injection, USP
One vial adapter
One administration needle
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Discard all components safely in an appropriate biohazard container.
Manufactured for: Ferring Pharmaceuticals Inc., Parsippany, NJ 07054. By: Rentschler Biotechnologie GmbH, Germany. Revised: Oct 2015
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 1325 patients with prostate cancer received FIRMAGON either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during FIRMAGON therapy included injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less.
FIRMAGON was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive FIRMAGON (subcutaneous) or leuprolide (intramuscular) monthly for 12 months.Adverse reactions reported in 5% of patients or more are shown in Table 1.
Table 1: Adverse Reactions Reported in ≥ 5% of Patients
in an Active Controlled Study
| FIRMAGON 240/160 mg (subcutaneous) N = 202 |
FIRMAGON 240/80 mg (subcutaneous) N = 207 |
Leuprolide 7.5 mg (intramuscular) N = 201 |
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| Percentage of subjects with adverse events | 83% | 79% | 78% |
| Body as a whole | |||
| Injection site adverse events | 44% | 35% | < 1% |
| Weight increase | 11% | 9% | 12% |
| Fatigue | 6% | 3% | 6% |
| Chills | 4% | 5% | 0% |
| Cardiovascular system | |||
| Hot flash | 26% | 26% | 21% |
| Hypertension | 7% | 6% | 4% |
| Musculoskeletal system | |||
| Back pain | 6% | 6% | 8% |
| Arthralgia | 4% | 5% | 9% |
| Urogenital system | |||
| Urinary tract infection | 2% | 5% | 9% |
| Digestive system | |||
| Increases in Transaminases and GGT | 10% | 10% | 5% |
| Constipation | 3% | 5% | 5% |
The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations ( < 1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix.
Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients.
In 1-5% of patients the following adverse reactions, not already listed, were considered related to FIRMAGON by the investigator:
Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia.
The following adverse reactions, not already listed, were reported to be drug-related by the investigator in ≥ 1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea.
The safety of FIRMAGON administered monthly was evaluated further in an extension study in 385 patients who completed the above active-controlled trial. Of the 385 patients, 251 patients continued treatment with FIRMAGON and 135 patients crossed over treatment from leuprolide to FIRMAGON. The median treatment duration on the extension study was approximately 43 months (range 1 to 58 months). The most common adverse reactions reported in > 10% of the patients were injection site reactions (e.g., pain, erythema, swelling, induration or inflammation), pyrexia, hot flush, weight loss or gain, fatigue, increases in serum levels of hepatic transaminases and GGT. One percent of patients had injection site infections including abscess. Hepatic laboratory abnormalities in the extension study included the following: Grade ½ elevations in hepatic transaminases occurred in 47% of patients and Grade 3 elevations occurred in 1% of patients.
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. It can be anticipated that long periods of medical castration in men will result in decreased bone density.
Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for 1 year. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation.
No drug-drug interaction studies were conducted.
Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the CYP450 system in vitro. Therefore, clinically significant CYP450 pharmacokinetic drug-drug interactions are unlikely.
Included as part of the PRECAUTIONS section.
Women who are or may become pregnant should not take FIRMAGON [see CONTRAINDICATIONS and Use In Specific Populations].
Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported postmarketing with Firmagon. In case of a serious hypersensitivity reaction, discontinue Firmagon immediately if the injection has not been completed, and manage as clinically indicated. Patients with a known history of serious hypersensitivity reactions to Firmagon should not be re-challenged with Firmagon.
Androgen deprivation therapy may prolong the QT 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.
In the randomized, active-controlled trial comparing FIRMAGON to leuprolide, periodic electrocardiograms were performed. Seven patients, three ( < 1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study, the median change for FIRMAGON was 12.3 msec and for leuprolide was 16.7 msec.
Therapy with FIRMAGON results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after FIRMAGON may be affected. The therapeutic effect of FIRMAGON should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Degarelix was administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg (about 9, 45 and 120% of the recommended human loading dose on a mg/m² basis). Long term treatment with degarelix at 25 mg/kg caused an increase in the combined incidence of benign hemangiomas plus malignant hemangiosarcomas in females.
Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg (about 5, 22 and 120% of the recommended human loading dose (240 mg) on a mg/m² basis). There was no statistically significant increase in tumor incidence associated with this treatment.
Degarelix did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration) nor in in vivo rodent bone marrow micronucleus tests.
Single degarelix doses of ≥ 1 mg/kg (about 5% of the clinical loading dose on a mg/m² basis) caused reversible infertility in male rats. Single doses of ≥ 0.1 mg/kg (about 0.5% of the clinical loading dose on a mg/m² basis) caused a decrease in fertility in female rats.
Category X [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
Women who are or may become pregnant should not take FIRMAGON.
When degarelix was given to rabbits during early organogenesis at doses of 0.002 mg/kg/day (about 0.02% of the clinical loading dose on a mg/m² basis), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of 0.006 mg/kg/day (about 0.05% of the clinical loading dose on a mg/m² basis) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of 0.0045 mg/kg/day (about 0.036% of the clinical loading dose on a mg/m² basis), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of 0.045 mg/kg/day (about 0.36% of the clinical loading dose on a mg/m² basis), there was an increase in the number of minor skeletal abnormalities and variants.
FIRMAGON is not indicated for use in women and is contraindicated in women who are or who may become pregnant. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from degarelix, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of subjects in clinical studies of FIRMAGON, 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine.
A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment [creatinine clearance (CrCL) 50-80 mL/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL < 50 mL/min.
Patients with hepatic impairment were excluded from the randomized trial.
A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 nonprostate cancer patients with either mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered.
Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.
There have been no reports of overdose with FIRMAGON. In the case of overdose, however, discontinue FIRMAGON, treat the patient symptomatically, and institute supportive measures.
As with all prescription drugs, this medicine should be kept out of the reach of children.
See Firmagon PATIENT INFORMATION
FIRMAGON is contraindicated in patients with known hypersensitivity to degarelix or to any of the product components. [see WARNINGS AND PRECAUTIONS].
Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman. Degarelix given to rabbits during organogenesis at doses that were 0.02% of the clinical loading dose (240 mg) on a mg/m² basis caused embryo/fetal lethality and abortion. When degarelix was given to female rats during organogenesis, at doses that were just 0.036% of the clinical loading dose on an mg/m² basis, there was an increase post implantation loss and a decrease in the number of live fetuses. 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.
Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, thereby reducing the release of gonadotropins and consequently testosterone.
A single dose of 240 mg FIRMAGON causes a decrease in the plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and subsequently testosterone.
FIRMAGON is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL.
Figure 1: Plasma Testosterone Levels from Day 0 to 364
for Degarelix 240 mg/80 mg (Median with Interquartile Ranges)
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FIRMAGON forms a depot upon subcutaneous administration, from which degarelix is released to the circulation. Following administration of FIRMAGON 240 mg at a product concentration of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, CV 83%) and the mean AUC was 1054 ng·day/mL (CV 35%). Typically Cmax occurred within 2 days after subcutaneous administration. In prostate cancer patients at a product concentration of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 240 mg. The pharmacokinetic behavior of the drug is strongly influenced by its concentration in the injection solution.
The distribution volume of degarelix after intravenous ( > 1 L/kg) or subcutaneous administration ( > 1000L) indicates that degarelix is distributed throughout total body water. In vitro plasma protein binding of degarelix is estimated to be approximately 90%.
Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the feces. No quantitatively significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate, inducer or inhibitor of the CYP450 or p-glycoprotein transporter systems.
Following subcutaneous administration of 240 mg FIRMAGON at a concentration of 40 mg/mL to prostate cancer patients, degarelix is eliminated in a biphasic fashion, with a median terminal half-life of approximately 53 days. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the FIRMAGON depot formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was renally excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary system in humans. Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9L/hr.
There was no effect of age, weight or race on the degarelix pharmacokinetic parameters or testosterone concentration.
The safety and efficacy of FIRMAGON were evaluated in an open-label, multi-center, randomized, parallel-group study in patients with prostate cancer A total of 620 patients were randomized to receive one of two FIRMAGON dosing regimens or leuprolide for one year:
Serum levels of testosterone were measured at screening, on Day 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study.
The clinical trial population (n=610) across all treatment arms had an overall median age of approximately 73 (range 50 to 98). The ethnic/racial distribution was 84% white, 6% black and 10% others. Disease stage was distributed approximately as follows: 20% metastatic, 29% locally advanced (T3/T4 Nx M0 or N1 M0), 31% localized (T1 or T2 N0 M0) and 20% classified as other (including patients whose disease metastatic status could not be determined definitively - or patients with PSA relapse after primary curative therapy). In addition, the median testosterone baseline value across treatment arms was approximately 400 ng/dL.
The primary objective was to demonstrate that FIRMAGON is effective with respect to achieving and maintaining testosterone suppression to castration levels (T ≤ 50 ng/dL), during 12 months treatment. The results are shown in Table 2.
Table 2: Medical Castration Rates (Testosterone
≤ 50 ng/dL) from Day 28 to Day 364
| FIRMAGON 240/160 mg N=202 |
FIRMAGON 240/80 mg N=207 |
Leuprolide 7.5 mg N=201 |
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| No. of Responders | 199 | 202 | 194 |
| Castration Rate (95% CIs)* | 98.3% (94.8; 99.4) |
97.2% (93.5; 98.8) |
96.4% (92.5; 98.2) |
| * Kaplan Meier estimates within group | |||
Percentage changes in testosterone from baseline to Day 28 (median with interquartile ranges) are shown in Figure 2 and the percentages of patients who attained the medical castration of testosterone ≤ 50 ng/dL are summarized in Table 3.
Figure 2: Percentage Change in Testosterone from
Baseline by Treatment Group until Day 28 (Median with Interquartile Ranges)
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Table 3: Percentage of Patients Attaining Testosterone
≤ 50 ng/dL within the First 28 Days
| FIRMAGON 240/160 mg N=202 |
FIRMAGON 240/80 mg N=207 |
Leuprolide 7.5 mg N=201 |
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| Day 1 | 44% | 52% | 0% |
| Day 3 | 96% | 96% | 0% |
| Day 7 | 99% | 99% | 1% |
| Day 14 | 99% | 99% | 18% |
| Day 28 | 99% | 100% | 100% |
In the clinical trial, PSA levels were monitored as a secondary endpoint. PSA levels were lowered by 64% two weeks after administration of FIRMAGON, 85% after one month, 95% after three months, and remained suppressed throughout the one year of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to a clinical benefit.
FIRMAGON
(FIRM-uh-gahn)
(degarelix for injection)
What is FIRMAGON?
FIRMAGON is a prescription medicine used in the treatment of advanced prostate cancer.
It is not known if FIRMAGON is safe or effective in children.
Who should not receive FIRMAGON?
Do not receive FIRMAGON if you are:
Talk to your healthcare provider before receiving FIRMAGON if you have any of these conditions.
Before receiving FIRMAGON, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How will I receive FIRMAGON?
You will receive an injection of FIRMAGON from your healthcare provider.
What are the possible side effects of FIRMAGON?
FIRMAGON can cause serious side effects, including:
The common side effects of FIRMAGON include:
Other side effects include decreased sex drive and erectile function problems.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of FIRMAGON.
Medicines are sometimes prescribed for conditions that are not mentioned in a Patient Information leaflet. Do not use FIRMAGON for a condition for which it was not prescribed. Do not give FIRMAGON to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about FIRMAGON that is written for health professionals.
What are the ingredients in FIRMAGON?
Active ingredient: degarelix (as acetate)
Inactive ingredient: mannitol
