Prescription Drugs

Plenaxis™ (abarelix) for Injectable Suspension WARNING Immediate-onset systemic allergic reactions, some resulting in hypotension and syncope, have occurred after administration of Plenaxis™ . These immediate-onset reactions have been reported to occur following any administration of Plenaxis™ , including after the initial dose. The cumulative risk of such a reaction increases with the duration of treatment (see WARNINGS). Following each injection of Plenaxis™ , patients should be observed for at least 30 minutes in the office and in the event of an allergic reaction, managed appropriately. Only physicians who have enrolled in the Plenaxis™ PLUS Program (Plenaxis™ User Safety Program), based on their attestation of qualifications and acceptance of prescribing responsibilities, may prescribe Plenaxis™ (See DOSAGE AND ADMINISTRATION and HOW SUPPLIED). Plenaxis™ is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia. The effectiveness of Plenaxis™ in suppressing serum testosterone to castrate levels decreases with continued dosing in some patients (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Effectiveness beyond 12 months has not been established. Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see WARNINGS). DESCRIPTION Abarelix for injectable suspension (Plenaxis™ ) is a synthetic decapeptide with potent antagonistic activity against naturally occurring gonadotropin releasing-hormone (GnRH). Plenaxis™ inhibits gonadotropin and related androgen production by directly and competitively blocking GnRH receptors in the pituitary. Abarelix is chemically described as acetyl-D-β-naphthylalanyl-D-4-chlorophenylalanyl- D-3-pyridylalanyl-L-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N(ε)-isopropyllysyl- L-prolyl-D-alanyl-amide. It is initially manufactured as an acetate water complex and converted to a carboxymethylcellulose (CMC) water complex in manufacturing the drug product. The molecular weight for abarelix anhydrous free base is 1416.06. The structural formula for abarelix peptide is: Abarelix for injectable suspension is supplied as a white to off-white sterile dry powder which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot suspension intended for intramuscular (IM) injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix CMC complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1.

INDICATIONS Plenaxis™ is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia. DOSAGE AND ADMINISTRATION For safety reasons, Plenaxis™ is approved with marketing restrictions. Only physicians who attest to the following qualifications and accept the following responsibilities, and on that basis enroll in PRAECIS PHARMACEUTICALS INCORPORATED's Plenaxis™ PLUS Program should prescribe Plenaxis™ . PRAECIS PHARMACEUTICALS INCORPORATED and its agents will provide Plenaxis™ to physicians enrolled in the Plenaxis™ PLUS Program. To enroll, physicians must attest that they are able and willing to: diagnose and manage advanced symptomatic prostate cancer. diagnose and treat allergic reactions, including anaphylaxis. have access to medication and equipment necessary to treat allergic reactions, including anaphylaxis. have patients observed for development of allergic reactions for 30 minutes following each administration of Plenaxis™ . understand the risks and benefits of palliative treatment with Plenaxis™ , including information from the Package Insert, Patient Information, and the Physician Attestation. educate the patients on the risks and benefits of treatment with Plenaxis™ and obtain the patient's signature on the Patient Information signature page, sign it, and place the original signed form in the patient's medical record, and give a copy of the Patient Information leaflet with the signed page to the patient. report serious adverse events, such as any immediate-onset systemic allergic event (including anaphylaxis, hypotension, and syncope) as soon as possible to PRAECIS PHARMACEUTICALS INCORPORATED at 1-866-PLENAXIS (1-866-753-6294) or to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088. understand that they may withdraw their enrollment in the Plenaxis™ Prescribing Program by a written statement submitted to PRAECIS PHARMACEUTICALS INCORPORATED (contact information below) or that PRAECIS PHARMACEUTICALS INCORPORATED may withdraw physicians from the Plenaxis™ PLUS Program if they do not meet the agreed upon responsibilities. To enroll in the Plenaxis™ Prescribing Program call 1-866-PLENAXIS (1-866-753-6294) or visit www.plenaxisplus.com. Dose: The recommended dose of Plenaxis™ is 100 mg administered intramuscularly to the buttock on Day 1, 15, 29 (week 4) and every 4 weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to Plenaxis™ administration, beginning on Day 29 and every 8 weeks thereafter. Directions for Reconstituting and Administering Plenaxis™ Read the instructions completely before performing reconstitution. The sterile powder for suspension is to be reconstituted in accordance with the following directions: Reconstitution Instructions for 1 Vial of Plenaxis™ to Provide a 100 mg (50 mg/mL) Dose as a Single IM Injection Use aseptic technique throughout. Prior to reconstitution, gently shake the vial of Plenaxis™ (abarelix for injectable suspension). Hold the vial at an angle (45 degrees) and tap lightly on table to break up any caking. Withdraw 2.2 mL of 0.9% Sodium Chloride Inj., USP using the enclosed 18 G x 1 ½” needle and a 3 cc syringe. Discard the remaining diluent. Picture 1 Keeping the vial upright, insert the needle all the way into the vial and inject the diluent quickly. Before withdrawing the needle, remove 2.2 mL of air. Shake immediately. Picture 2 Shake for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to reduce foaming and swirl the vial occasionally. Again, shake for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to reduce foaming and swirl the vial occasionally. Picture 3 Do not reinject the air into the vial. Locate a second injection spot on the stopper, and then insert the 18 G needle. Invert the vial and draw up some of the suspension into the syringe and without removing the needle from the vial reinject it at any remaining solids in the vial. Repeat the process until all solids are dispersed. Swirl the vial before withdrawal and withdraw the entire contents (at least 2 mL) by positioning the needle at a 45 degree angle as shown in the picture. Picture 4 Pull the plunger back to recover the residual suspension in the 18 G x1½” needle. Exchange the 18 G x 1 ½” needle with the enclosed 22 G x 1½” Safety Glide™ injection needle. Picture 5 Insert the needle at the desired injection site, pull the plunger back to check for back-flow of blood. If blood flows into the syringe, do not inject at this site. Select another injection site. Deliver the entire reconstituted suspension intramuscularly immediately. Picture 6 Observe the patient after injection for 30 minutes for any sign of an allergic-type response. Plenaxis™ does not contain a preservative and should be administered within 1 hour following reconstitution. Storage Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F), USP Controlled Room Temperature. HOW SUPPLIED The physician must attest to meeting the qualifications and accepting the responsibilities in the DOSAGE AND ADMINISTRATION section of this package insert by submitting the Physician's Attestation form to PRAECIS PHARMACEUTICALS INCORPORATED to be enrolled in the Plenaxis™ PLUS Program. PRAECIS PHARMACEUTICALS INCORPORATED and its agents will only provide Plenaxis™ to physicians enrolled in the Plenaxis™ Prescribing Program. Plenaxis™ vials are not to be resold or redistributed. Plenaxis™ (abarelix for injectable suspension) is supplied as a single-dose, preservativefree vial containing 113 mg of abarelix (anhydrous free base peptide) as an abarelix CMC complex, a sterile powder (NDC 68158-149-01) which, when reconstituted with 2.2 mL of 0.9% sodium chloride solution, yields a 2 mL delivered dose of 100 mg (50 mg/mL). Each single use dispensing pack also contains: a single-use 10 mL diluent vial of 0.9% Sodium Chloride Injection, USP, one 3 cc syringe with an 18 gauge 1½ inch needle and one 22 gauge 1½ inch Safety Glide™ injection needle. Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451-1420. 02-01

PATIENT INFORMATION Plenaxis™ (plen·AK·sis) (abarelix for injectable suspension) Read the Patient Information that comes with PlenaxisTM before you start getting injections. Sign the last page if you agree with treatment with Plenaxis™ . (Your signature will be required to start treatment.) What is the most important information I should know about Plenaxis™ ? Plenaxis™ can cause serious or life threatening allergic reactions that may need emergency medical treatment right away. These serious reactions may include: low blood pressure and fainting (shock) swelling of your face, eyelids, tongue, or throat asthma, wheezing, or other breathing problems such as chest tightness or shortness of breath Your chances of getting a serious or life threatening allergic reaction may increase with each Plenaxis™ injection that you get. If a serious or life threatening allergic reaction happens, it is usually soon after getting a Plenaxis™ injection. Therefore, you must wait in your doctor's office or health care facility for 30 minutes after each Plenaxis™ injection. Tell your doctor right away if you feel any warmth, redness, light-headedness, swelling or thickness in your throat. This could mean you are having a serious allergic reaction. Only doctors signed up with PRAECIS PHARMACEUTICALS INCORPORATED can prescribe PlenaxisTM because they know about treating prostate cancer and allergic reactions from Plenaxis™ . Plenaxis™ is only for treating advanced prostate cancer when a patient cannot have or refuses other treatments for prostate cancer, such as other hormone treatments or surgery to remove the testicles, and there are serious symptoms from the prostate cancer such as the cancer is near or pressing on the spinal cord, causing problems urinating or blockage of urine from the kidneys or bladder, or there is very bad bone pain even when taking narcotic pain medicines. Plenaxis™ may not keep working for everyone over time, so doctors should do blood tests about every 8 weeks to make sure Plenaxis™ is working by keeping your testosterone hormone level low. What is Plenaxis™ ? Plenaxis™ is a type of medicine called a gonadotropin-releasing hormone (GnRH) antagonist that lowers the male hormone testosterone in your blood. Testosterone makes most prostate cancers grow. Other ways to treat your prostate cancer are taking other hormone medicines to lower testosterone or surgery to remove your testicles. Plenaxis™ is used when these other ways to treat prostate cancer cannot be used or are refused. Who should not take Plenaxis™ ? Do not take Plenaxis™ if you are: a woman. There is no approved use of Plenaxis™ in women. Plenaxis™ can cause serious allergic reactions. Plenaxis™ can cause the death of an unborn child in a pregnant woman. Plenaxis™ may also pass into breast milk. a child under the age of 18 years. There are no studies that show that Plenaxis™ is safe or effective for use in children for any condition. allergic to any of the ingredients in Plenaxis™ . The ingredients include abarelix and carboxymethylcellulose. The mixing solution contains sodium chloride. Tell your doctor before taking a Plenaxis™ injection: if you or any family members have a rare heart condition known as prolongation of the QTc interval about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Plenaxis™ has not been studied with other medicines. Plenaxis™ and some of your other medicines may affect each other and could cause side effects. How do I take Plenaxis™ ? Plenaxis™ is only prescribed by doctors who are part of the Plenaxis™ PLUS Program (Plenaxis™ User Safety Program) run by PRAECIS PHARMACEUTICALS INCORPORATED. Plenaxis™ is given as an injection in your buttocks. Your doctor or nurse gives a Plenaxis™ injection every two weeks for the first month, and then every four weeks (every 28 days). It is important that you keep your appointment with your doctor's office for the times when your injection is due. Always wait in your doctor's office for 30 minutes after getting each Plenaxis™ injection. (See “What is the most important information I should know about Plenaxis™ ?”) Your doctor should do regular blood tests about every 8 weeks to check your testosterone level to see if Plenaxis™ is working for you. If you weigh more than 225 pounds, there may be a greater chance that Plenaxis™ may stop working. Your doctor should also do blood tests to check on your liver because Plenaxis™ may cause changes in your liver tests. What are the possible side effects of Plenaxis™ ? Plenaxis™ can cause: serious allergic or life threatening reactions. (See “What is the most important information I should know about Plenaxis™ ?”) allergic skin reactions such as a rash, hives, itching, tingling, and redness (flushing). A skin reaction may happen right away after injection with Plenaxis™ or several days later. Tell your doctor right away if you get an allergic skin reaction or rash after a Plenaxis™ injection. a change in heart rhythm called prolongation of the QTc interval. This condition may change the way your heart beats, cause fainting and even death in some patients. changes in liver function, which usually go away after you stop taking Plenaxis™ . Your doctor should do blood tests to check your liver function before you start getting Plenaxis™ and during your treatment with it. loss in bone mineral density with extended treatment. Low bone mineral density can lead to thinning of the bones (osteoporosis). The most common side effects of Plenaxis™ are: hot flashes problems sleeping pain, including back pain breast enlargement or breast pain constipation Talk to your doctor if you get a side effect that bothers you. These are not all the possible side effects of Plenaxis™ . For more information ask your doctor. General Information about Plenaxis™ This leaflet summarizes the most important information about Plenaxis™ . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Plenaxis™ that is written for health professionals. Patient Signature for Treatment with Plenaxis™ I have read and understood the Patient Information leaflet. My doctor has answered my questions about treatment with Plenaxis™ for treating advanced prostate cancer. I cannot have or refuse treatments for my prostate cancer, such as other hormone treatments or surgery to remove my testicles, and my doctor has told me I have serious signs and/or symptoms from my prostate cancer such as the cancer is near or pressing on the spinal cord, or it is causing problems urinating or blockage of urine from the kidneys or bladder, or I have very bad bone pain even when taking narcotic pain medicines. Plenaxis™ can cause serious allergic reactions right after an injection. Therefore, after each injection I will wait in my doctor's office or health care facility for 30 minutes so if I have a serious allergic reaction, I can be treated. I know that my doctor should be getting blood tests to check my testosterone level about every 8 weeks to check if Plenaxis™ is working for me. I understand that I can only get Plenaxis™ from doctors who have signed up with the company that makes Plenaxis™ . My signature shows that I have read, understood and agree with all the statements above. I allow my doctor to begin treatment with Plenaxis™ . I only need to sign this page one time to start my treatment. Name of Patient (Print):________________________________________________ Signature of Patient:________________________________Date:_______________ Name of Physician (Print):_______________________________________________ Signature of Physician ____________________________Date:_________________ Instructions to Physician: As part of beginning Plenaxis™ treatment, give the patient a copy of the entire leaflet with the signed page, and put the original patient signature page in the patient's medical chart. This information leaflet has been approved by the U.S. Food and Drug Administration.

OVERDOSE The maximum tolerated dose of Plenaxis™ has not been determined. The maximum dose used in clinical studies was 150 mg. There have been no reports of accidental overdose with Plenaxis™ . CONTRAINDICATIONS Plenaxis™ is contraindicated in those patients with a known hypersensitivity to any of the components in abarelix for injectable suspension. Plenaxis™ is not indicated in women or pediatric patients. In addition, Plenaxis™ may cause fetal harm if administered to a pregnant woman.

SIDE EFFECTS Immediate-Onset Systemic Allergic Reactions: See BOXED WARNINGS and WARNINGS In the single study of Plenaxis™ conducted in men with advanced symptomatic prostate cancer, adverse events reported by ≥ 10% of patients are listed in Table 4. Adverse events are listed without regard to causality. Causality is often difficult to assess in elderly patients with multiple co-morbidities and prostate cancer. Table 4: Adverse Events in ≥ 10% of Patients in the Advanced Symptomatic Prostate Cancer Study (without regard for causality). Preferred Term Plenaxis™ N=81 n (%) Hot flushes* 64 (79) Sleep disturbance* 36 (44) Pain 25 (31) Breast enlargement* 24 (30) Breast pain/nipple tenderness* 16 (20) Back pain 14 (17) Constipation 12 (15) Peripheral edema 12 (15) Dizziness 10 (12) Headache 10 (12) Upper respiratory tract infection 10 (12) Diarrhea 9 (11) Dysuria 8 (10) Fatigue 8 (10) Micturition frequency 8 (10) Nausea 8 (10) Urinary retention 8 (10) Urinary tract infection 8 (10) * Pharmacological consequence of androgen deprivation Changes in Laboratory Values Clinically meaningful increases in serum transaminases were seen in a small percentage of patients in both treatment groups in each active-controlled Plenaxis™ study. In Study 1 and Study 2 combined, the percentage of Plenaxis™ patients reporting serum ALT > 2.5 times upper limit of normal or > 200 U./L was 8.2% and 1.8%, respectively. The percentage reporting serum AST > 2.5 times upper limit of normal or > 200 U/L was 3.1% and 0.8%, respectively. Similar results were reported for active comparators. Slight decrease in hemoglobin, a pharmacological consequence of castration, were observed in patients receiving Plenaxis™ and active comparator. Mean increases in serum triglycerides of approximately 10% were seen in Plenaxis™ -treated patients. DRUG INTERACTIONS No formal drug/drug interaction studies with Plenaxis™ were performed. Cytochrome P-450 is not known to be involved in the metabolism of Plenaxis™ . Plenaxis™ is highly bound to plasma proteins (96 to 99%). Laboratory Tests Response to Plenaxis™ should be monitored by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see WARNINGS). Serum transaminase levels should be obtained before starting treatment with Plenaxis™ and periodically during treatment. Periodic measurement of serum PSA levels may also be considered.

WARNINGS Immediate-Onset Systemic Allergic Reactions (See BOXED WARNINGS) In the clinical trial of patients with advanced, symptomatic prostate cancer, 3 of 81 (3.7%) patients experienced an immediate-onset systemic allergic reaction within minutes of receiving Plenaxis™ . The allergic reactions were urticaria (Day 15), urticaria and pruritis (Day 29), and hypotension and syncope (Day 141). Patients should be monitored for at least 30 minutes after each injection of Plenaxis™ . In the event of an allergic reaction associated with hypotension and/or syncope, appropriate supportive measures such as leg elevation, oxygen, IV fluids, antihistamines, corticosteroids, and epinephrine (alone or in combination) should be employed. From all the prostate cancer clinical trials with Plenaxis™ (mostly in men without advanced, symptomatic disease), immediate-onset systemic allergic reactions (occurring within 30 minutes of dosing), were observed in 1.1% (15/1397) of patients dosed with Plenaxis™ . In 14/15 patients who experienced an allergic reaction, each developed symptoms within 8 minutes of injection. The cumulative risk of such a reaction increased with duration of treatment. The cumulative rates (and 95% confidence intervals) on Days 56, 141, 365 and 676 were 0.51%, (0.13%, 0.88%) 0.80% (0.30%, 1.29%), 1.24% (0.43%, 2.04%) and 2.91% (0.87, 4.95%), respectively. Seven patients experienced hypotension or syncope as part of their allergic reaction, representing 0.5% of all patients. The cumulative rates (and 95% confidence intervals) for these types of reactions on Days 56, 141, 365, and 617 after the initial dose were 0.22% (0.0%, 0.46%), 0.32% (0.0%, 0.64%), 0.61% (0.0%, 1.24%) and 1.67% (0.07, 3.28%), respectively. Decrease in Effectiveness With Continued Dosing A decrease in overall effectiveness with increased duration of treatment, as measured by failure to maintain suppression of serum testosterone below 50 ng/dL, was noted (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 after the initial dose and every 8 weeks thereafter. Prolongation of the QT Interval Because Plenaxis™ may prolong the QT interval (see CLINICAL PHARMACOLOGY, Pharmacodynamics), physicians should carefully consider whether the risks of Plenaxis™ outweigh the benefits in patients with baseline QTc values > 450 msec (e.g. congenital QT prolongation) and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications. PRECAUTIONS General Decreased effectiveness in patients > 225 pounds: The decrease in overall effectiveness of Plenaxis™ with increased duration of treatment is greater in patients who weigh more than 225 pounds. Strict monitoring of serum testosterone in these patients is warranted. Monitoring of liver function: Clinically meaningful transaminase elevations were observed in some patients who received Plenaxis™ or comparator drugs. Serum transaminase levels should be obtained before starting treatment with Plenaxis™ and periodically during treatment (see ADVERSE REACTIONS). Decrease in bone mineral density: Extended treatment with GnRH antagonists and LHRH agonists may result in a decrease in bone mineral density. Geriatric Use Prostate cancer occurs primarily in an older patient population. Clinical studies with Plenaxis™ have been conducted primarily in patients ≥ 65 years of age. No difference in the safety profile, when examined as a function of age, was apparent. Pediatric Use The safety and effectiveness of Plenaxis™ in pediatric patients have not been studied. Plenaxis™ is not indicated for use in pediatric patients. Carcinogenesis, Mutagenesis, Impairment of Fertility Plenaxis™ was not carcinogenic to mice or rats when administered as a subcutaneous depot every 28 days for 2 years at doses up to 300 mg/kg in mice and 100 mg/kg in rats. Systemic drug exposures, as measured by mean Cmax, were approximately 210-278-fold for mice and 21-32-fold for rats the human exposure following subcutaneous depot administration of 100 mg. Plenaxis™ was not mutagenic in the in vitro bacterial Ames assay or forward mutation assay in mouse lymphoma, or clastogenic in the in vivo mouse micronucleus assay. No effects on mating or fertility in male and female rats given 1 mg/kg subcutaneous Plenaxis™ , a dose 0.114-fold the human therapeutic dose of 100 mg based on body surface area. Mating and fertility were significantly decreased at doses of 3 and 10 mg/kg (0.34-fold and 1.135-fold, respectively, the human therapeutic dose of 100 mg based on body surface area), but the effects were reversible. Pregnancy Category X (see CONTRAINDICATIONS) Embryolethality occurred in pregnant rats administered a single subcutaneous dose of Plenaxis™ up to 3 mg/kg (0.228-fold the human therapeutic dose of 100 mg based on body surface area). In rabbits a dose-related increase in fetal resorptions and reduced viability was observed at doses up to 30 mg/kg (6.81-fold the human therapeutic dose of 100 mg based on body surface area). No teratogenic effects were observed in rats or rabbits up to doses of 3 mg/kg or 30 mg/kg, respectively. A no-observable-adverse effect- level (NOAEL) dose was 0.3 mg/kg (approximately 0.034-fold the human therapeutic dose of 100 mg based on body surface area) in rats and < 0.01 mg/kg ( < 0.0023-fold the human therapeutic dose of 100 mg based on body surface area) in rabbits. Nursing Mothers It is not known whether Plenaxis™ is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Plenaxis™ on lactation and/or the breastfed child have not been determined, Plenaxis™ should not be used by nursing mothers.