Plenaxis

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

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.

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.

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.

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.

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).

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.

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).

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.

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™.

A single dose (100 mg IM) of Plenaxis™ was given to 14 healthy male volunteers 52 to 75 years of age, with body weight of 61.6 to 110.5 kg, and the pharmacokinetic information is provided in Table 1

Table 1: Mean ± SD Pharmacokinetic Parameter Values of 100 mg of Plenaxis™ Following a Single IM Injection (n = 14)

Absorption

Following IM administration of 100 mg of Plenaxis™ , abarelix is absorbed slowly with a mean peak concentration of 43.4 ng/mL observed approximately 3 days after the injection.

Distribution

The apparent volume of distribution during the terminal phase determined after IM administration of Plenaxis™ was 4040 ± 1607 liters, implying that abarelix probably distributes extensively within the body.

Metabolism

In vitro hepatocyte (rat, monkey, human) studies and in vivo studies in rats and monkeys showed that the major metabolites of abarelix were formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix were found either in vitro or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix.

Excretion

In humans, approximately 13% of unchanged abarelix was recovered in urine after a 15 μg/kg IM injection; there were no detectable metabolites in urine. Renal clearance of abarelix was 14.4 L/day (or 10 mL/min) after administration of 100 mg Plenaxis™.