CAVERJECT

CAVERJECT contains alprostadil, a synthetic form of prostaglandin E 1 (PGE 1 ), and is designated chemically as (11α,13E,15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. The molecular weight is 354.49. Alprostadil is a white to off-white crystalline powder with a melting point between 115°C and 116° C. CAVERJECT is available as a sterile freeze-dried powder for intracavernosal use in sizes: 20 mcg and 40 mcg per vial. When reconstituted as directed with 1 mL of bacteriostatic water for injection, the volume of the reconstituted solution is 1.13 mL. Each mL of CAVERJECT contains 20.5 mcg or 41.1 mcg of alprostadil depending on vial strength, 172 mg of lactose, 47 mcg of sodium citrate and 8.4 mg of benzyl alcohol. The deliverable amount of alprostadil is 20 mcg or 40 mcg per mL because approximately 0.5 mcg for the 20 mcg strength and 1.1 mcg for the 40 mcg strength is lost due to adsorption to the vial and syringe. During manufacture, the pH of alprostadil for injection was adjusted with hydrochloric acid and/or sodium hydroxide before lyophilization. The structural formula of alprostadil is represented below: Chemical Structure

CAVERJECT is a prostaglandin E1 agonist indicated • For the treatment of erectile dysfunction ( 1.1 ). • As an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction ( 1.2 ). 1.1 Erectile Dysfunction CAVERJECT is indicated for the treatment of erectile dysfunction. 1.2 Diagnostic Test CAVERJECT is indicated as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.

• Determine the most suitable dose and presentation of CAVERJECT to use. Use a new vial for each dose of CAVERJECT ( 2.1 ). • Administer first intracavernosal injections in the health care provider’s office and titrate the dose for each patient to the lowest effective dose ( 2.1 ). • Instruct the patient on proper use and assess that they are well trained in the self-injection technique prior to initiation of at-home use ( 2.1 ). • Recommended dosage for erectile dysfunction ( 2.2 ): • Erectile dysfunction of vasculogenic, psychogenic, or mixed etiology: Initiate dosing with 2.5 mcg • Erectile dysfunction of pure neurogenic etiology (spinal cord injury): Initiate dosing with 1.25 mcg • Follow dose titration procedures for each type of erectile dysfunction and determine the maintenance dosage for patient home use in the health care provider’s office ( 2.2 ). • The recommended frequency of injection is no more than 3 times weekly, with at least 24 hours between each dose ( 2.2 ). • While on self-injection treatment, the patient should visit the prescribing health care provider’s office every 3 months to assess the efficacy and safety of the therapy ( 2.1 ). • Follow the procedure for CAVERJECT syringe preparation ( 2.3 ). • Follow procedure for CAVERJECT intracavernosal injection administration ( 2.4 ). • To diagnose erectile dysfunction (pharmacologic testing), inject CAVERJECT intracavernosally and monitor patients for the occurrence of an erection ( 2.2 ). 2.1 Important Dosage and Administration Instructions • Alprostadil is available in different strengths and presentations. Determine the most suitable dose and presentation for each patient. • CAVERJECT is available in single-dose vials containing 20 mcg or 40 mcg of alprostadil. Make sure a new, correct strength vial of CAVERJECT is used for each patient dosage preparation. • Titrate the dose of CAVERJECT for each patient to the lowest effective dose. • CAVERJECT doses greater than 60 mcg are not recommended. • Administer the first injections of CAVERJECT in the health care provider’s office by medically trained personnel. • Instruct the patient on proper use and assess that they are well trained in the self-injection technique prior to initiation of home use. Refer to the Patient Information and Instructions for Use. • Re-evaluate patients regularly (every 3 months or as clinically appropriate) and determine if dosage adjustments are needed. 2.2 Recommended Dosage for Erectile Dysfunction Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology • Initiate dosing with 2.5 mcg of CAVERJECT intracavernosally, as recommended [see Dosage and Administration (2.4) ] . • If there is a partial response at 2.5 mcg, administer another dose of 2.5 mcg within 1 hour. Use a new vial for each dose of CAVERJECT. • During titration, no more than 2 doses should be given within a 24-hour period. • If additional titration is required, administer doses in increments of 5 to 10 mcg at least 24 hours apart. • The optimal dose should produce an erection suitable for intercourse that does not exceed a duration of 1 hour. • The patient must stay in the health care provider’s office until complete detumescence occurs. Repeat the titration as necessary until the optimal dose is achieved. Doses greater than 60 mcg are not recommended. Erectile Dysfunction of Pure Neurogenic Etiology (e.g., Spinal Cord Injury). • Initiate dosing with 1.25 mcg of CAVERJECT intracavernosally, as recommended [see Dosage and Administration (2.4 )] . • If there is a partial response at 1.25 mcg, administer another dose of 1.25 mcg within 1 hour. Use a new vial for each dose of CAVERJECT. • If additional titration is required, administer a dose of 5 mcg at least 24 hours later. • During titration, no more than 2 doses should be given within a 24-hour period. • The optimal dose should produce an erection suitable for intercourse that does not exceed a duration of 1 hour. • The patient must stay in the health care provider’s office until complete detumescence occurs. Repeat the titration as necessary until the optimal dose is achieved. Doses greater than 60 mcg are not recommended. Maintenance Dosage for Patient Home Use • Once the dose of CAVERJECT has been determined in the health care provider’s office, additional dose adjustment may be required after consultation with the health care provider. Adjust the dose in accordance with the titration guidelines described above. • The recommended frequency of injection is no more than 3 times weekly, with at least 24 hours between each dose. Adjunct to the Diagnosis of Erectile Dysfunction As an adjunct to the diagnosis of erectile dysfunction, inject CAVERJECT intracavernosally and monitor patients for the occurrence of an erection. Extensions of this testing are the use of CAVERJECT as an adjunct to laboratory investigations, such as duplex or Doppler ultrasound imaging. For any of these tests, use a single dose of CAVERJECT that induces a rigid erection. Use the dose regimen for ‘ Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology ’ above. 2.3 Preparation Instructions Supplies Needed and Not Supplied With CAVERJECT • 1 mL of the diluent (bacteriostatic water for injection) • 1 mL to 3 mL syringe, dependent on the titrated dose • 21 to 27 gauge needle for reconstitution • 29 or 30 gauge one-half inch needle for injection • alcohol swabs Reconstitution Instructions • CAVERJECT vial(s): Using the correct strength vial containing 20 mcg or 40 mcg of CAVERJECT, use a 1 mL to 3 mL syringe, a 21 to 27 gauge needle, and 1 mL of the diluent (bacteriostatic water for injection) for reconstitution. Reconstitution results in CAVERJECT 20 mcg/mL or 40 mcg/mL. • Visually inspect the solution in the vial for particulate matter and discoloration. Do not use the solution if it is cloudy, colored or contains particles. Table 1: Volume of CAVERJECT Solution to Inject using 1 mL syringe 20 mcg Vial 40 mcg Vial Dose Volume to Inject Dose Volume to Inject 1.25 mcg 0.06 mL 1.25 mcg --- 2.5 mcg 0.125 mL 2.5 mcg --- 5 mcg 0.25 mL 5 mcg 0.125 mL 10 mcg 0.5 mL 10 mcg 0.25 mL 15 mcg 0.75 mL 15 mcg 0.375 mL 20 mcg 1 mL 20 mcg 0.5 mL 25 mcg --- 25 mcg 0.625 mL 30 mcg --- 30 mcg 0.75 mL 40 mcg --- 40 mcg 1 mL • Draw the dose of CAVERJECT into the syringe. • Replace the needle used for reconstitution with a 29 or 30 gauge one-half inch needle prior to injection. • The reconstituted solution should be used within 24 hours when stored at or below 25°C (77°F). Refer to the Patient Information and Instructions for Use in the FDA-approved patient labeling for the complete detailed instructions on reconstitution and needle preparation steps. 2.4 Administration Instructions • Use a 29 or 30 gauge one-half inch needle for injecting each dose. • The patient should be in a sitting or slightly reclined position when injecting a dose. • Retract the foreskin in uncircumcised patients. • Grasp the head of the penis with the thumb and forefinger and stretch it lengthwise along the thigh. • The site of injection is either the right or left lateral penis. See Figures A and B below. Figure A Figure B • Wipe the intended injection site with an alcohol swab prior to injection. • Insert needle perpendicular to the long dorsolateral penile axis in the proximal third of penis. Avoid angulation of the syringe and do not bend the needle. • Avoid visible veins during injection. • With each use of CAVERJECT, alternate the side of the penis that is injected. • Compress the site of injection with an alcohol swab or sterile gauze for 5 minutes. • CAVERJECT is intended for single patient use only and should be discarded after use. Figure A Figure B

CAVERJECT is contraindicated: • in men who have a known hypersensitivity to the drug [see Adverse Reactions (6.1) ] • in men who have conditions that predispose them to priapism, such as sickle cell anemia or sickle cell trait, multiple myeloma, or leukemia [see Warnings and Precautions (5.1) ] • for the treatment of erectile dysfunction in men with fibrotic conditions of the penis, such as anatomical deformation, angulation, cavernosal fibrosis, or Peyronie's disease [see Warnings and Precautions (5.2) ] • in men with penile implants. • Men who have known hypersensitivity to the drug ( 4 ). • Men who have conditions that predispose them to priapism, such as sickle cell anemia or sickle cell trait, multiple myeloma, or leukemia ( 4 ). • Treatment of erectile dysfunction in men with fibrotic conditions of the penis, such as anatomical deformation, angulation, cavernosal fibrosis, or Peyronie's disease ( 4 ). • Men with penile implants ( 4 ).

The following are described elsewhere in the labeling: • Prolonged Erection and Priapism [see Warnings and Precautions (5.1) ] • Penile Fibrosis [see Warnings and Precautions (5.2) ] The most common (≥10%) adverse reaction is penile pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (1-800-438-1985 and www.pfizer.com ) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 clinical practice. Local Adverse Reactions: Local adverse reactions derived from 1861 patients in clinical studies of CAVERJECT, including an 18-month, open-label study, are shown in Table 2. Table 2. Local Adverse Reactions Reported by ≥ 1% of Patients Treated with CAVERJECT for up to 18 Months Penile pain 37% Prolonged erection 4% Penile fibrosis 3% Injection site hematoma 3% Penis disorder Penis disorder includes: numbness, irritation, sensitivity, pruritus, erythema, skin tear, discoloration, itching. 3% Injection site ecchymosis 2% Penile rash 1% Penile edema 1% The following local adverse reactions were reported in < 1% of patients: injection site hemorrhage, injection site inflammation, injection site itching, injection site swelling, injection site edema, urethral bleeding, penile warmth, numbness, irritation, sensitivity, pruritus, erythema, painful erection, and abnormal ejaculation. In these studies, no local adverse reactions were reported in the 294 patients who received placebo, except for penile pain (2%). Penile Pain: In the majority of the cases, penile pain was rated mild or moderate in intensity. Three percent of patients discontinued treatment because of penile pain Prolonged Erection/Priapism: Prolonged erection was defined as an erection that lasted for 4 to 6 hours; priapism was defined as an erection that lasted 6 hours or longer. In clinical studies the frequency of prolonged erection after CAVERJECT was 4%, while the frequency of priapism was 0.4% [ see Warnings and Precautions (5.1) ] . Penile Hematoma/Ecchymosis: In clinical studies, the frequency of penile hematoma and ecchymosis was 3% and 2%, respectively. Systemic Adverse Reactions : Systemic adverse reactions reported by ≥ 1% of subjects in clinical studies of CAVERJECT included: dizziness (1%). The following systemic adverse reactions were reported in < 1% of patients: testicular pain, scrotal edema, hematuria, pelvic pain, hypotension, vasodilation, vasovagal reaction, diaphoresis, rash, and non-application site pruritus. Three patients (0.2%) discontinued due to symptomatic hypotension. No systemic adverse reactions were reported in the 294 patients who received placebo. In addition to the adverse reactions observed for CAVERJECT, the following adverse reactions have been reported in clinical studies of CAVERJECT IMPULSE: CAVERJECT IMPULSE was evaluated in 87 patients in an open-label crossover study of 6 weeks treatment duration that compared the formulation of alprostadil for injection contained in CAVERJECT IMPULSE with the formulation contained in CAVERJECT. Doses used in this study ranged from 2.5 mcg to 20 mcg. Adverse reactions reported for the CAVERJECT IMPULSE formulation included: penis disorder (4.6%), prolonged erection (1.1%), injection site erythema (1.1%), rash (1.1%), dizziness (1.1%), and hematospermia (1.1%). Penis disorder included penile pain, post-injection pain, and pain with erection. CAVERJECT IMPULSE was also evaluated in 63 patients in a single-dose, double-blind, crossover study that compared CAVERJECT IMPULSE with CAVERJECT. Doses used in this study ranged from 2.5 mcg to 20 mcg. Adverse reactions reported for the CAVERJECT IMPULSE formulation included: penile pain (1.6%) and pruritis (1.6%). 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of CAVERJECT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Injury and procedural complications: Needle breakage during administration of CAVERJECT. In some instances, surgical removal of the needle was required.

The potential for pharmacokinetic drug-drug interactions between alprostadil and other agents administered orally or intracavernosally has not been formally studied [see Warnings and Precautions (5.6) ] .

Store CAVERJECT 20 mcg vials between 20°C to 25°C (68°F to 77°F). The reconstituted solution should be used within 24 hours when stored at or below 25°C (77°F) and not refrigerated or frozen. Store CAVERJECT 40 mcg vials between 2°C to 8°C (36° to 46°F) until dispensed. Once dispensed, vials should be stored at or below 25°C (77°F) for up to 3 months or until the expiration date, whichever occurs first. The reconstituted solution should be used within 24 hours when stored at or below 25°C (77°F) and not refrigerated or frozen. When reconstituted and used as directed, the deliverable amount of alprostadil is 20 micrograms or 40 micrograms, respectively. Only bacteriostatic water for injection, should be used when reconstituting CAVERJECT. CAVERJECT is available in the following packages: Package of six 20 mcg vials NDC 0009-3701-05 Package of six 40 mcg vials NDC 0009-7686-04 The following supplies are needed for injection and are not supplied with CAVERJECT: • 1 mL of the diluent (bacteriostatic water for injection) • 1 mL to 3 mL syringe, dependent on the titrated dose • 21 to 27 gauge needle for reconstitution • 29 or 30 gauge one-half inch needle for injection • alcohol swabs