ALPROSTADIL: 2,800 Adverse Event Reports & Safety Profile

DESCRIPTION edex ® (alprostadil for injection) is a sterile, pyrogen-free powder containing alprostadil in an alfadex (α-cyclodextrin) inclusion complex. Alprostadil is an endogenous substance known as prostaglandin E 1 (PGE 1 ). edex ® is supplied in single-dose, dual-chamber cartridges. edex ® is lyophilized in single-dose, dual-chamber cartridges intended for use with the reusable edex ® injection device. One chamber of the cartridge contains alprostadil, alfadex and lactose as a sterile, pyrogen-free powder. The other chamber contains 1.075 mL of sterile 0.9% sodium chloride. The edex ® cartridges are supplied in three strengths: 10-mcg cartridge (10.75 mcg alprostadil, 347.55 mcg α-cyclodextrin, 51.06 mg lactose); 20-mcg cartridge (21.5 mcg alprostadil, 695.2 mcg α-cyclodextrin, 51.06 mg lactose); 40-mcg cartridge (43 mcg alprostadil, 1,390.3 mcg α-cyclodextrin, 51.06 mg lactose). The edex ® injection device is used to reconstitute the sterile powder in one chamber with the sterile 0.9% sodium chloride in the other chamber. After reconstitution, the edex ® injection device is used to administer the intracavernous injection of alprostadil. The chemical name for alprostadil is (1R,2R,3R)-3-Hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopentane heptanoic acid. The empirical formula is C 20 H 34 O 5 and the molecular weight is 354.49. The chemical structure is: The α-cyclodextrin inclusion complex improves the water solubility of alprostadil. The empirical formula of α-cyclodextrin is C 36 H 60 O 30 and the molecular weight is 972.85. The chemical structure is: Alprostadil alfadex is a white, odorless, hygroscopic powder. It is freely soluble in water and practically insoluble in ethanol, ethyl acetate and ether. After reconstitution, the active ingredient, alprostadil, immediately dissociates from the α-cyclodextrin inclusion complex. The reconstituted solution is clear and colorless and has a pH between 4.0 and 8.0. When the single-dose, dual-chamber cartridge containing either 10.75, 21.5, or 43 mcg of alprostadil is placed into the edex ® injection device and reconstituted, the deliverable amount of alprostadil in each milliliter is 10, 20 or 40 mcg, respectively. alprostadil chemical structure α-cyclodextrin chemical structure

INDICATIONS AND USAGE PROSTIN VR PEDIATRIC Sterile Solution is indicated for palliative, not definitive, therapy to temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in neonates who have congenital heart defects and who depend upon the patent ductus for survival. Such congenital heart defects include pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, or transposition of the great vessels with or without other defects. In infants with restricted pulmonary blood flow, the increase in blood oxygenation is inversely proportional to pretreatment pO 2 values; that is, patients with low pO 2 values respond best, and patients with pO 2 values of 40 torr or more usually have little response. PROSTIN VR PEDIATRIC should be administered only by trained personnel in facilities that provide pediatric intensive care.

AND ADMINISTRATION

• Determine the most suitable dose and presentation of CAVERJECT to use. Use a new syringe 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 ): o Erectile dysfunction of vasculogenic, psychogenic, or mixed etiology: Initiate dosing with 2.5 mcg o 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 procedure for CAVERJECT IMPULSE syringe preparation ( 2.3 ).
• Follow the procedure for CAVERJECT IMPULSE administration ( 2.4 ).
• To diagnose erectile dysfunction (pharmacologic testing), inject CAVERJECT IMPULSE 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. Use a new syringe for each dose of CAVERJECT.
• Titrate the dose of CAVERJECT IMPULSE for each patient to the lowest effective dose.
• CAVERJECT IMPULSE doses greater than 60 mcg are not recommended.
• Administer the first doses of CAVERJECT IMPULSE 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 IMPULSE intracavernousally 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.
• 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 (Spinal Cord Injury):

• Initiate dosing with 1.25 mcg of alprostadil using CAVERJECT.
• If there is a partial response, administer another dose of CAVERJECT of 1.25 mcg within 1 hour.
• No more than 2 doses during initial titration should be given within a 24-hour period.
• If additional titration is required, administer a dose of 5 mcg at least 24 hours later.
• 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 IMPULSE 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 To diagnose erectile dysfunction (pharmacologic testing), inject CAVERJECT IMPULSE 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 imaging. For any of these tests, use a single dose of CAVERJECT IMPULSE that induces a rigid erection. Use the dose regimen for ‘Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology’ above.

2.3 Syringe Preparation Instructions 1. Select the CAVERJECT IMPULSE syringe based upon dose to be administered.

Syringe Strength Reconstituted Concentration Dosages

Available for Delivery after Reconstitution 10 mcg 10 mcg/0.5 mL 2.5 mcg 5 mcg 7.5 mcg 10 mcg 20 mcg 20 mcg/0.5 mL 5 mcg 10 mcg 15 mcg 20 mcg 2. Open the sealed plastic tray. Remove the syringe, the needle assembly, and the alcohol swabs from the tray. The syringe has a dose window and a plunger. The needle assembly is a sealed unit that contains the outer protective cap, the inner protective cap, and the superfine needle. 3. Use the alcohol swab to wipe the rubber membrane at the tip of the syringe. Pick up the needle assembly, grasp the paper tab, and peel off the paper cover (the lid). 4. Hold the needle assembly by the cap and press the needle assembly onto the tip of the syringe. Turn it clockwise until the needle assembly is firmly locked into place. 5. Remove the outer protective cap from the needle by twisting it clockwise. Do not yet remove the inner protective cap, the thin plastic tube that directly covers the needle. 6. Hold the syringe system with the needle pointing upward. The plunger rod should still be in the fully extended position, with all of the threads visible. Slowly rotate the plunger rod clockwise until it goes all the way in and stops. Do not push on the plunger while trying to rotate it. 7. Turn the syringe upside down several times to make sure the solution is evenly mixed. The solution should be clear. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The product should not be used if particulate matter or discoloration are present. 8. Hold the syringe with the needle upward and carefully remove the inner protective cap from the needle. Lightly tap the glass cartridge a few times with your finger until any large bubbles disappear up into the tip. With the syringe pointed upward, push in the plunger rod until it stops to push any air out. 9. To set the dose: locate the dose window on the syringe and then slowly turn the plunger rod clockwise until the correct dose number appears in the center of the window. The syringe is now ready for use. If you pass the correct number, keep turning the plunger in the same direction until the correct number comes around again – do not try to turn it backward. 10. After reconstitution, the syringe should be used within 24 hours when stored between 36 to 77°F (2°C to 25°C). Do not freeze. CAVERJECT IMPULSE is for single use only. Discard the injection delivery system and any remaining solution after use.

2.4 Administration Instructions

• Administer CAVERJECT IMPUSLE intracavernosally along the dorso-lateral aspect of the proximal third of the penis.

See

Figures A and B below. Figure A Figure B

• Wipe the intended injection site with an alcohol swab prior to injection.
• Avoid visible veins during injection.
• Alternate the side of the penis that is injected and the site of injection.
• Compress the site of injection with an alcohol swab or sterile gauze for 5 minutes.
• Each CAVERJECT IMPULSE syringe is intended for single use only (one dose only) and should be discarded after use. Injection site Top side

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 ).

ADVERSE REACTIONS edex ® , administered by intracavernous injection in doses ranging from 1 to 40 mcg per injection for periods up to 24 months, has been evaluated in clinical trials for safety in over 1,065 patients with erectile dysfunction. Discontinuation of therapy due to a side effect in clinical trials was required in approximately 9% of patients treated with edex ® and in <1% of patients treated with placebo.

Local Adverse Reactions

The following local adverse reactions were reported in studies including 1,065 patients treated with edex ® for up to two years.

Penile Pain

With use of up to 24 months, penile pain was reported at least once by 29% of patients during injection, 35% of patients during erection, and by 30% of patients after erection. On a per injection basis, 15% of injections were associated with penile pain. Penile pain was judged by patients to be mild in intensity for 80% of painful injections, moderate in intensity for 16% of painful injections, and severe in intensity for 4% of painful injections. The frequency of penile pain reports decreased over time; 41% of the patients experienced pain during the first 2 months and 3% of the patients experienced pain during months 21 to 24. In placebo-controlled studies, penile pain was reported by 31% of patients after edex ® and by 9% of patients after placebo injection.

Prolonged Erection/Priapism

Prolonged erections greater than four hours in duration occurred in 4% of all patients treated up to 24 months. In placebo-controlled studies, 3% of patients treated with edex ® and <1% of patients treated with placebo reported prolonged erections greater than four hours. The incidence of priapism (erections greater than 6 hours in duration) was <1% with long-term use for up to 24 months. In the majority of cases, spontaneous detumescence occurred. A higher incidence of prolonged erections was found in younger patients (<40 years), non-diabetic patients, and patients with psychogenic etiology of erectile dysfunction ( See WARNINGS ). Hematoma/Ecchymosis In patients treated with edex ® for up to 24 months, local bleeding, hematoma, and ecchymosis were observed in 15%, 5%, and 4% of patients, respectively. In placebo-controlled studies, the frequency of local bleeding was 6% with injection of edex ® and 3% with injection of placebo. In most cases, these reactions were attributed to faulty injection technique.

Local Adverse Reactions

Reported by ≥1% of Patients All Study Periods 1 Local Reaction edex® Local Reaction edex® N = 1065 N = 1065 n (%) n (%) Penile pain during injection 305 (29)

Ecchymosis

44 (4) Penile pain during erection 368 (35) Penile angulation 72 (7) Penile pain after erection 317 (30) Penile fibrosis 52 (5) Penile pain (other) 2 116 (11) Cavernous body fibrosis 20 (2) Prolonged erection Peyronie's disease 11 (1) > 4 ≤ 6 Hours 44 (4) Faulty injection technique 3 59 (6) > 6 Hours 6 (<1) Penis disorder 28 (3)

Bleeding

158 (15)

Erythema

17 (2)

Hematoma

56 (5) 1 Protocol Numbers KU-620-001, KU-620-002, KU-620-003, F-8653. 2 Penile pain reported without an association to injection site or erection, such as pain in penis and scrotum, pain in glans penis, and burning penile pain. 3 Examples include injection into glans penis, urethra or subcutaneously.

Systemic Adverse Experiences

The following systemic adverse experiences were reported in controlled and uncontrolled studies in ≥1% of patients treated for up to 24 months with edex ® .

Systemic Adverse Experiences

Reported by ≥1% of Patients 1 BODY SYSTEM edex ® BODY SYSTEM edex ® BODY SYSTEM edex ® Adverse Experience N = 1065 Adverse Experience N = 1065 Adverse Experience N = 1065 n (%) n (%) n (%)

Respiratory Cardiovascular Urogenital

Upper respiratory tract Hypertension 17 (2) Prostate disorder 15 (1) infection 58 (5) Myocardial infarction 13 (1) Testicular pain 13 (1)

Sinusitis

14 (1) Abnormal ECG 12 (1) Inguinal hernia 11 (1) BODY AS A WHOLE Influenza-like symptoms 35 (3) METABOLIC/NUTRITIONAL DERMATOLOGIC Headache 20 (2)

Hypertriglyceridemia

17 (2) Skin disorder 14 (1)

Infection

18 (2)

Hypercholesterolemia

12 (1)

Special Senses

Pain 16 (2)

Hyperglycemia

12 (1) Abnormal vision 11 (1)

Musculoskeletal

Back pain 23 (2) Leg pain 13 (1) 1 Protocol Numbers KU-620-001, KU-620-002, KU-620-003, F-8653. Hemodynamic changes, manifested as increases or decreases in blood pressure and pulse rate, were observed during clinical studies but did not appear to be dose-dependent. Four patients (<1%) reported clinical symptoms of hypotension such as dizziness or syncope. edex ® had no clinically important effect on serum or urine laboratory tests. Post-Marketing Adverse Experiences Needle breakage.

AND PRECAUTIONS

• Prolonged erection and priapism have occurred in patients receiving CAVERJECT. To minimize the chances of this occurring, titrate CAVERJECT IMPULSE slowly to the lowest effective dose ( 2.1 ). Advise patients to seek immediate medical assistance for an erection that persists longer than 4 hours ( 5.1 ).
• Penile fibrosis has occurred in patients receiving CAVERJECT. Follow patients regularly to detect signs of penile fibrosis. Discontinue in patients who develop penile angulation or cavernosal fibrosis ( 5.2 ).
• Hypotension - injections of CAVERJECT IMPULSE can lead to increased peripheral blood levels of alprostadil, especially in patients with significant corpora cavernosa venous leakage. Avoid use in patients with known cavernosal venous leakage ( 5.3 ).
• Injection site bleeding may occur in patients taking anticoagulants, such as warfarin or heparin. Compress the site of injection with an alcohol swab or sterile gauze for 5 minutes ( 5.4 ).
• Cardiovascular risk related to underlying medical conditions - Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy ( 5.5 ).
• Risks of use in combination with other vasoactive medications injected intracavernosally - Safety and efficacy of combinations of CAVERJECT and other vasoactive agents have not been systematically studied. Use of such combinations is not recommended ( 5.6 ).
• Risk of needle breakage – A superfine needle is used for CAVERJECT IMPULSE and cases of needle breakage have been reported. Careful instruction in proper patient handling and injection techniques may minimize this risk ( 5.7 ).
• Benzyl alcohol – Serious and fatal adverse reactions can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved formulations in infusion solutions, including CAVERJECT IMPULSE. CAVERJECT IMPULSE is not indicated in neonates and infants ( 5.8 ).
• Counsel patients about sexually transmitted diseases . Counsel patients about the protective measures necessary to guard against sexually transmitted disease including the Human Immunodeficiency Virus (HIV) ( 5.9 ).

5.1 Prolonged Erection and Priapism Prolonged erection, defined as erection lasting between 4 to 6 hours in duration, occurred in 4% of 1,861 patients treated up to 18 months in studies of CAVERJECT. The incidence of priapism (erections lasting more than 6 hours in duration) was 0.4%. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. To minimize the chances of prolonged erection or priapism, titrate CAVERJECT IMPULSE to the lowest effective dose [ see Dosage and Administration (2.1 ]. In addition, do not use CAVERJECT IMPULSE in patients who have conditions that predispose them to priapism, such as sickle cell anemia or sickle cell trait, multiple myeloma, or leukemia <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.2 Penile Fibrosis The overall incidence of penile fibrosis reported in clinical studies with CAVERJECT was 3%. In one self-injection clinical study where duration of use was up to 18 months, the incidence of penile fibrosis was 7.8%. Physical examination of the penis should be performed periodically to detect signs of penile fibrosis. Treatment with CAVERJECT IMPULSE should be discontinued in patients who develop penile angulation or cavernosal fibrosis.

5.3 Hypotension Intracavernous injections of CAVERJECT IMPULSE can increase peripheral blood levels of alprostadil which can result in hypotension. Avoid use of CAVERJECT IMPULSE in patients with known cavernosal venous leakage.

5.4 Injection Site Bleeding When Used with Anticoagulants Patients on anticoagulants, such as warfarin or heparin, may have increased propensity for injection site bleeding after intracavernosal injection with CAVERJECT IMPULSE. Compress the site of injection with an alcohol swab or sterile gauze for 5 minutes.

5.5 Cardiovascular Risk Related to Underlying Medical Conditions There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including CAVERJECT IMPULSE, generally should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. In addition, the evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

5.6 Risks of Use in Combination with Other Vasoactive Medications Injected Intracavernosally The safety and efficacy of combinations of CAVERJECT IMPULSE and other vasoactive agents injected intracavernosally have not been established in clinical studies. The risks of prolonged erection, priapism, and hypotension may be increased.

5.7 Needle Breakage CAVERJECT IMPULSE uses a superfine (29 gauge) needle for administration. As with all superfine needles, the possibility of needle breakage exists. Needle breakage, with a portion of the needle remaining in the penis, has been reported and, in some cases, has required hospitalization and surgical removal. Careful instruction in proper patient handling and injection techniques may minimize the potential for needle breakage <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Adverse Reactions (6.2) ]</span> .

5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol The preservative benzyl alcohol contained in CAVERJECT IMPULSE has been associated with serious adverse events, including the &quot;gasping syndrome&quot;, and death in pediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys&apos; capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. CAVERJECT IMPULSE is not indicated for use in pediatric patients.

5.9 Counsel Patients About Sexually Transmitted Diseases The use of CAVERJECT IMPULSE offers no protection against sexually transmitted diseases. Counsel patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV).

PRECAUTIONS General 1) Intracavernous injections of edex ® can lead to increased peripheral blood levels of PGE 1 and its metabolites, especially in those patients with significant corpora cavernosa venous leakage. Increased peripheral blood levels of PGE 1 and its metabolites may lead to hypotension and/or dizziness. 2) Regular follow-up of patients, with careful examination of the penis at the start of therapy and at regular intervals (e.g. 3 months), is strongly recommended to identify any penile changes. The overall incidence of penile fibrosis, including Peyronie's disease, reported in clinical studies up to 24 months with edex ® was 7.8%. Treatment with edex ® should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease. Treatment can be resumed if the penile abnormality subsides. 3) The safety and efficacy of combinations of edex ® and other vasoactive agents have not been systematically studied. Therefore, the use of such combinations is not recommended. 4) After injection of the edex ® solution, compression of the injection site for five minutes, or until bleeding stops, is necessary. Patients on anticoagulants, such as warfarin or heparin, may have increased propensity for bleeding after intracavernous injection. 5) Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy with edex ® . 6) edex ® uses a superfine (29 gauge) needle. As with all superfine needles, the possibility of needle breakage exists. Careful instruction in proper patient handling and injection techniques may minimize the potential for needle breakage. 7) The patient should be instructed not to reuse or to share needles or cartridges. As with all prescription medicines, the patient should not allow anyone else to use his medicine. 8)

Cardiovascular Risk

Related to Underlying Medical Conditions There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including edex ® , generally should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. In addition, the evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

Drug Interactions

The pharmacodynamic interaction between heparin (5,000 units) and alprostadil intravenous infusion (90 mcg over 3 hours) was investigated. The results indicate significant changes in partial thromboplastin time (140% increase) and thrombin time (120% increase). Therefore, caution should be exercised with concomitant administration of heparin and edex ® . (Also, see Drug-Drug Interactions in CLINICAL PHARMACOLOGY, Pharmacokinetics .) Information for Patients To ensure safe and effective use of edex ® , the patient should be thoroughly instructed and trained in the self-injection technique before he begins intracavernous treatment with edex ® at home. The desirable dose should be established in the physician's office. The instructions for preparation of the edex ® solution should be carefully followed. The reconstituted solution may initially appear cloudy due to small air bubbles. Do not use the solution if it remains cloudy, contains precipitates, or is discolored. The reconstituted solution should be gently mixed, not shaken. A patient information pamphlet is included in each package of edex ® cartridges. edex ® should be used immediately after reconstitution. The patient should follow the instructions in the patient information pamphlet to limit the possibility of bacterial contamination. The reconstituted cartridge is designed for one use only and should be discarded after use. The edex ® cartridge contains a solid layer or Iyophilized cake of dry white powder approximately 3/8" in thickness. A normal cake may appear cracked or crumbled. If the cartridge is damaged, the cake may shrink in size. Do not use the cartridge if it appears damaged or the cake is substantially reduced in size. If the dosage prescribed is less than 1 mL of edex ® solution, excess solution will be expelled through the needle as the plunger is pushed and the upper rim of the top stopper reaches the correct volume mark for the prescribed dose. The needle must be properly discarded after use; it must not be reused or shared with other persons. The dose of edex ® that is established in the physician's office should not be changed by the patient without consulting the physician. The patient may expect an erection to occur within 5 to 20 minutes. A standard treatment goal is to produce an erection lasting no longer than 1 hour. edex ® should be used no more than 3 times per week, with at least 24 hours between each use. Patients should be aware of possible side effects of therapy with edex ® ; the most frequently occurring is penile pain during and/or after injection, usually mild to moderate in severity. A potentially serious adverse reaction with intracavernous therapy is priapism. Accordingly, the patient should be instructed to contact the physician's office immediately or, if unavailable, to seek immediate medical assistance if an erection persists for longer than 6 hours. The patient should report any penile pain that was not present before or that increased in intensity, as well as the occurrence of nodules or hard tissue in the penis to his physician as soon as possible. As with any injection, infection is possible. Patients should be instructed to report to the physician any penile redness, swelling, tenderness or curvature of the erect penis. The patient must visit the physician's office for regular checkups for assessment of the therapeutic benefit and safety of treatment with edex ® . Note: Individuals who are sexually active should be counseled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). Use of intracavernous edex ® offers no protection from the transmission of sexually transmitted or blood-borne diseases. The injection of edex ® can induce a small amount of bleeding at the site of injection. In patients infected with blood-borne diseases, this could increase the risk of transmission of blood-borne diseases between partners. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have not been conducted. Alprostadil showed no evidence of mutagenicity in three in vitro assays including the AMES bacterial reverse mutation assay, a forward gene mutation assay in Chinese hamster lung (V79) cells, and a chromosome aberration assay in human peripheral lymphocytes. Alprostadil did not produce damage to chromosomes or the mitotic apparatus in the in vivo rat micronucleus test. Alprostadil did not cause any adverse effects on fertility or general reproductive performance when administered intraperitoneally to male or female rats at dose levels from 2 to 200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose (MRHD) on a body weight basis. The human dose of edex ® is <1 mcg/kg (MRHD is 40 mcg and the calculation assumes a 60-kg subject). Pregnancy, Nursing Mothers and Pediatric Use edex ® is not indicated for use in women or pediatric patients.

Geriatric

Use Of the approximately 1,065 patients who entered the in-office dose-titration period in clinical studies, 25% were 65 years or older. In clinical studies, geriatric patients required, on average, higher minimally effective doses and had a higher rate of lack of effect (optimum dose not determined). Overall differences in safety were not observed between these geriatric patients and younger patients. Geriatric patients should be dosed and titrated according to the same DOSAGE AND ADMINISTRATION recommendations as younger patients, and the lowest possible effective dose should always be used. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Drug Interactions The pharmacodynamic interaction between heparin (5,000 units) and alprostadil intravenous infusion (90 mcg over 3 hours) was investigated. The results indicate significant changes in partial thromboplastin time (140% increase) and thrombin time (120% increase). Therefore, caution should be exercised with concomitant administration of heparin and edex ® . (Also, see Drug-Drug Interactions in CLINICAL PHARMACOLOGY, Pharmacokinetics .)