Caverject Impulse

U.S. Pharmaceuticals

CaverJect Impulse Dual Chamber System alprostadil for injection

FULL PRESCRIBING INFORMATION: CONTENTS*

• CAVERJECT IMPULSE DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacokinetics
  • Pharmacokinetics in Special Populations
• CLINICAL STUDIES
  • Study 1
  • Study 2
  • Study 3
• INDICATION AND USAGE
• CAVERJECT IMPULSE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General Precautions
  • Information for the Patient
  • Carcinogenesis, Mutagenesis, and Impairment of Fertility
  • Pregnancy, Nursing Mothers, and Pediatric Use
  • Geriatric Use
• CAVERJECT IMPULSE ADVERSE REACTIONS
  • Local Adverse Reactions
  • Penile Pain
  • Prolonged Erection/Priapism
  • Hematoma/Ecchymosis
  • Systemic Adverse Events
  • Post-Marketing Surveillance
• OVERDOSAGE
• CAVERJECT IMPULSE DOSAGE AND ADMINISTRATION
  • Initial Titration in Physician's Office
  • Maintenance Therapy
  • CAVERJECT as an Adjunct to the Diagnosis of Erectile Dysfunction
  • General Procedure for Solution Preparation
  • Caution
• HOW SUPPLIED
• Patient Instructions For:
• INSTRUCTIONS FOR USE
• PRINCIPAL DISPLAY PANEL - 10 microgram Syringe Label
• PRINCIPAL DISPLAY PANEL - 10 microgram Syringe Carton
• PRINCIPAL DISPLAY PANEL - 20 microgram Syringe Label
• PRINCIPAL DISPLAY PANEL - 20 microgram Syringe Carton

FULL PRESCRIBING INFORMATION

For Intracavernosal Use

CAVERJECT IMPULSE DESCRIPTION

CAVERJECT contains alprostadil as the naturally occurring form of prostaglandin E₁ (PGE₁) 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° and 116°C. Its solubility at 35°C is 8000 micrograms (mcg) per 100 milliliter double distilled water.

The structural formula of alprostadil is represented below:

CAVERJECT IMPULSE is available as a disposable, single-dose, dual chamber syringe system. The system includes a glass cartridge which contains sterile, freeze-dried alprostadil in the front chamber and sterile bacteriostatic water for injection in the rear chamber. The alprostadil is reconstituted with the sterile bacteriostatic water just before injection. CAVERJECT IMPULSE is available in two strengths for intracavernosal administration:

10 microgram – The reconstituted solution has a volume of 0.64 mL. The delivered volume, 0.5 mL, contains 10 micrograms (mcg) of alprostadil, 324.7 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol.

20 microgram – The reconstituted solution has a volume of 0.64 mL. The delivered volume, 0.5 mL, contains 20 micrograms (mcg) of alprostadil, 649.3 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol.

When necessary, the pH of the alprostadil for injection was adjusted with hydrochloric acid and/or sodium hydroxide before lyophilization.

CLINICAL PHARMACOLOGY

Alprostadil has a wide variety of pharmacological actions; vasodilation and inhibition of platelet aggregation are among the most notable of these effects. In most animal species tested, alprostadil relaxed retractor penis and corpus cavernosum urethrae in vitro. Alprostadil also relaxed isolated preparations of human corpus cavernosum and spongiosum, as well as cavernous arterial segments contracted by either noradrenaline or PGF_2a in vitro. In pigtail monkeys (Macaca nemestrina), alprostadil increased cavernous arterial blood flow in vivo. The degree and duration of cavernous smooth muscle relaxation in this animal model was dose-dependent.

Alprostadil induces erection by relaxation of trabecular smooth muscle and by dilation of cavernosal arteries. This leads to expansion of lacunar spaces and entrapment of blood by compressing the venules against the tunica albuginea, a process referred to as the corporal veno-occlusive mechanism.

Pharmacokinetics

Absorption

For the treatment of erectile dysfunction, alprostadil is administered by injection into the corpora cavernosa. The absolute bioavailability of alprostadil has not been determined.

Distribution

Following intracavernosal injection of 20 mcg alprostadil, mean peripheral plasma concentrations of alprostadil at 30 and 60 minutes after injection (89 and 102 picograms/mL, respectively) were not significantly greater than baseline levels of endogenous alprostadil (96 picograms/mL). Plasma levels of alprostadil were measured using a radioimmunoassay method. Alprostadil is bound in plasma primarily to albumin (81% bound) and to a lesser extent I-globulin IV-4 fraction (55% bound). No significant binding to erythrocytes or white blood cells was observed.

Metabolism

Alprostadil is rapidly converted to compounds, which are further metabolized prior to excretion. Following intravenous administration, approximately 80% of circulating alprostadil is metabolized in one pass through the lungs, primarily by beta- and omega-oxidation. Hence, any alprostadil entering the systemic circulation following intracavernosal injection is very rapidly metabolized. Following intracavernosal injection of 20 mcg alprostadil, peripheral levels of the major circulating metabolite, 13,14-dihydro-15-oxo-PGE₁, increased to reach a peak 30 minutes after injection and returned to pre-dose levels by 60 minutes after injection.

Excretion

The metabolites of alprostadil are excreted primarily by the kidney, with almost 90% of an administered intravenous dose excreted in urine within 24 hours post-dose. The remainder of the dose is excreted in the feces. There is no evidence of tissue retention of alprostadil or its metabolites following intravenous administration.

Pharmacokinetics in Special Populations

Geriatric

The potential effect of age on the pharmacokinetics of alprostadil has not been formally evaluated. In patients with acute respiratory distress syndrome (ARDS), the mean (± SD) pulmonary extraction of alprostadil was 72% ± 15% in 11 elderly patients aged 65 years or older (mean, 71 ± 6 years) and 65% ± 20% in 6 young patients aged 35 years or younger (mean, 28 ± 5 years).

Pediatric

Alprostadil plasma concentrations were measured in 10 neonates (gestational age of 34 weeks in 2 infants and 38 to 40 weeks in 8 infants) receiving steady-state intravenous infusions of alprostadil to treat underlying cardiac malformations. Infusion rates of alprostadil ranged from 5 to 50 (median, 45) nanograms/kilogram/minute, resulting in alprostadil plasma concentrations ranging between 22 and 530 (median, 56) picograms/mL. The wide range of alprostadil plasma concentrations in neonates reflects high variability in individual clearances of alprostadil in this patient population.

Gender

The potential influence of gender on the pharmacokinetics of alprostadil has not been formally studied in healthy subjects. Two studies determined the pulmonary extraction of alprostadil following intravascular administration in 23 patients with ARDS. The mean (± SD) pulmonary extraction was 66% ± 20% in 17 male patients and 69% ± 18% in 6 female patients, suggesting that the pharmacokinetics of alprostadil are not influenced by gender.

Race

The potential influence of race in the pharmacokinetics of alprostadil has not been formally evaluated.

Renal and Hepatic Insufficiency

The pharmacokinetics of alprostadil have not been formally studied in patients with renal or hepatic insufficiency.

Pulmonary Disease

The pulmonary extraction of alprostadil following intravascular administration was reduced by 15% (66 ± 3.2% vs. 78 ± 2.4%) in patients with ARDS compared with a control group of patients with normal respiratory function who were undergoing cardiopulmonary bypass surgery. Pulmonary clearance was found to vary as a function of cardiac output and pulmonary intrinsic clearance in a group of 14 patients with ARDS or at risk of developing ARDS following trauma or sepsis. In this study, the extraction efficiency of alprostadil ranged from subnormal (11%) to normal (90%), with an overall mean of 67%.

Drug-Drug Interactions

The potential for pharmacokinetic drug-drug interactions between alprostadil and other agents has not been formally studied.

CLINICAL STUDIES

The safety and efficacy of CAVERJECT Sterile Powder was investigated in men with a diagnosis of erectile dysfunction due to psychogenic, vasculogenic, neurogenic, and/or mixed etiology in two well-controlled studies (Study 1 and Study 2) and in one 6-month open-label study (Study 3).

Study 1

One hundred fifty-three men with a mean age of 53 years (range 23–69 years) were enrolled. The study had three phases: a 2.5 week double-blind, in-office randomized crossover phase in which each man received placebo or 2.5 mcg, 5 mcg, 7.5 mcg, or 10 mcg of CAVERJECT Sterile Powder; a 2 week open-label, in-office dose-titration phase to identify the optimum home-use dose (the latter dose was defined as a dose inducing an erection sufficient for penetration and lasting ≤ 60 minutes); and a 4-week open-label, self-injection phase. In the double-blind phase, each dose of CAVERJECT was significantly more effective than placebo by clinical evaluation ("full penile rigidity") and by RigiScan criteria (≥ 70% rigidity for at least 10 minutes); there was no response to placebo. The percentage of responders increased with increasing doses of CAVERJECT. The overall response in the dose-ranging phases was 76% (117/153) by clinical evaluation and 51% (78/152) by RigiScan criteria. The optimum dose for self-injection ranged from 1.25 to 65 mcg (median 20 mcg). Seventy-three percent of the injections in 102 men who self-injected CAVERJECT resulted in satisfactory intercourse. Seventy-five percent of the patients remained on the dose identified during the dose-ranging phase; 17% and 8% of the patients slightly decreased or increased the dose, respectively. The mean duration of erection per injection was 70.8 minutes.

Study 2

Two hundred ninety-six men with a mean age of 53.8 years (range 21–74 years) were enrolled in this parallel-design, double-blind study. The men were randomly assigned to one of five groups and received either a single dose of placebo, 2.5 mcg, 5 mcg, 10 mcg, or 20 mcg of CAVERJECT Sterile Powder. No patient responded to placebo. The differences in the response rates in both the clinical and the RigiScan evaluations between each of the doses of CAVERJECT and placebo were statistically significant. There was also a statistically significant dose-response relationship with higher clinical response rates and higher RigiScan response rates with increasing doses of CAVERJECT (with exception of the 10-mcg dose). The mean duration of erection after injection ranged from 12 minutes after the 2.5-mcg dose to 44 minutes after the 20-mcg dose and the relationship was linear (p = .025, linear regression analysis).

Study 3

The safety and efficacy of CAVERJECT Sterile Powder was evaluated in a 6-month, open-label study in 683 men with a mean age of 58 years (range 20–79 years). The optimum dose of CAVERJECT was established by titration in 89% of men (606/683). Four hundred seventy-one men (69%) completed the 6-month study. At the start of the study, the mean dose was 17.7 mcg of CAVERJECT and at the end of the study it was 20.7 mcg. Eighty-seven percent of the 13,762 injections of CAVERJECT, administered by self-injection by the men in the study, resulted in satisfactory sexual activity. The mean duration of erection was 67.5 minutes.

The formulation of alprostadil contained in CAVERJECT IMPULSE includes the inactive excipient alpha cyclodextrin. This formulation was compared with CAVERJECT Sterile Powder in 87 men in a single-blind, crossover study designed to evaluate efficacy and safety. The doses used by the patients in the study ranged from 2.5 mcg to 20 mcg and were the same for both formulations. The efficacy of the two formulations was shown to be comparable, as assessed by the 30-point erectile function (EF) domain score from the International Index of Erectile Function (IIEF) and by a physician-assessment score for erectile response. The mean EF domain scores for CAVERJECT Sterile Powder and the formulation contained in CAVERJECT IMPULSE were 26.6 (SD=5.3) and 27.6 (SD=3.8), respectively. The mean physician's assessment scores for CAVERJECT Sterile Powder and the formulation contained in CAVERJECT IMPULSE were 2.6 (SD=0.6) and 2.7 (SD=0.5), respectively, based on a scale of 0 (no tumescence) to 3 (full rigidity).

INDICATION AND USAGE

CAVERJECT (CAVERJECT IMPULSE and CAVERJECT Sterile Powder) is indicated for the treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology.

Intracavernosal CAVERJECT is also indicated as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.

CAVERJECT IMPULSE CONTRAINDICATIONS

CAVERJECT should not be used in patients who have a known hypersensitivity to the drug, in patients who have conditions that might predispose them to priapism, such as sickle cell anemia or trait, multiple myeloma, or leukemia, or in patients with anatomical deformation of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease. Patients with penile implants should not be treated with CAVERJECT.

CAVERJECT is intended for use in adult men only.

CAVERJECT is not indicated for use in children or newborns.

CAVERJECT should not be used in men for whom sexual activity is inadvisable or contraindicated.

WARNINGS

Prolonged erection defined as erection lasting > 4 to ≤ 6 hours in duration occurred in 4% of 1,861 patients treated up to 18 months in studies of CAVERJECT Sterile Powder. The incidence of priapism (erections lasting > 6 hours in duration) was 0.4% with the same length of use. Pharmacologic intervention and/or aspiration of blood from the corpora cavernosum was performed in 2 of the 7 patients with priapism. To minimize the chances of prolonged erection or priapism, CAVERJECT should be titrated slowly to the lowest effective dose (see DOSAGE AND ADMINISTRATION). The patient must be instructed to immediately report to his prescribing physician, or, if unavailable, to seek immediate medical assistance for any erection that persists longer than 4 hours. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

PRECAUTIONS

General Precautions

• CAVERJECT IMPULSE is designed for one use only. Following a single use, the injection delivery system and any remaining solution should be properly discarded.
• The overall incidence of penile fibrosis, including Peyronie's disease, reported in clinical studies with CAVERJECT Sterile Powder was 3%. In one self-injection clinical study where duration of use was up to 18 months, the incidence of fibrosis was 7.8%.
  Regular follow-up of patients, with careful examination of the penis, is strongly recommended to detect signs of penile fibrosis. Treatment with CAVERJECT should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease.
• Intracavernous injections of CAVERJECT can lead to increased peripheral blood levels of PGE₁ and its metabolites, especially in those patients with significant corpora cavernosa venous leakage. Increased peripheral blood levels of PGE₁ and its metabolites may lead to hypotension and/or dizziness.
• Patients on anticoagulants, such as warfarin or heparin, may have increased propensity for bleeding after intracavernosal injection.
• Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy with CAVERJECT.
• The safety and efficacy of combinations of CAVERJECT and other vasoactive agents have not been systematically studied. Therefore, the use of such combinations is not recommended.
• CAVERJECT IMPULSE 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.
• The patient should be instructed not to re-use or to share needles or syringes. As with all prescription medicines, the patient should not allow anyone else to use his medicine.

Information for the Patient

To ensure safe and effective use of CAVERJECT, the patient should be thoroughly instructed and trained in the self-injection technique before he begins intracavernosal treatment with CAVERJECT at home. The desirable dose should be established in the physician's office.

Any reconstituted solution with precipitates or discoloration should be discarded. The CAVERJECT IMPULSE syringe system is designed for one use only and should be discarded after use. The delivery system and the needle must be properly discarded after use. Needles must not be re-used or shared with other persons. Patient instructions for administration are included in each package of CAVERJECT IMPULSE.

The dose of CAVERJECT 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. Generally, CAVERJECT 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 CAVERJECT; the most frequently occurring is penile pain after injection, usually mild to moderate in severity. A potentially serious adverse reaction with intracavernosal 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 4 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, an infection is a possibility. 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 check-ups for assessment of the therapeutic benefit and safety of treatment with CAVERJECT.

Note: Use of intracavernosal CAVERJECT offers no protection from the transmission of sexually transmitted diseases. Individuals who use CAVERJECT 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).

The injection of CAVERJECT can induce a small amount of bleeding at the site of injection (see ADVERSE REACTIONS section hematoma, ecchymosis, hemorrhage 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.

In clinical trials, concomitant use of agents such as antihypertensive drugs, diuretics, antidiabetic agents (including insulin), or non-steroidal anti-inflammatory drugs had no effect on the efficacy or safety of CAVERJECT.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies have not been conducted. Rat reproductive studies indicate that alprostadil at doses of up to 0.2 mg/kg/day does not adversely affect or alter rat spermatogenesis, providing a 200-fold margin of safety compared with the usual human doses. The following battery of mutagenicity assays revealed no potential for mutagenesis: bacterial mutation (Ames), alkaline elution, rat micronucleus, sister chromatid exchange, CHO/HGPRT mammalian cell forward gene mutation, and unscheduled DNA synthesis (UDS).

A 1-year irritancy study was conducted in three groups of 5 male Cynomolgus monkeys injected intracavernosally twice weekly with either vehicle or 3 or 8.25 mcg of alprostadil/ injection. An additional two groups of 6 monkeys each were injected with vehicle or with 8.25 mcg/injection twice weekly as described previously plus they received multiple doses during weeks 44, 48, and 52. Three monkeys from each group were retained for a 4-week recovery period. There was no evidence of drug-related penile irritancy or nonpenile tissue lesions, which could be directly related to alprostadil. The irritancy, which was noted for control and treated monkeys, was considered to be a result of the injection procedure itself, and any lesions noted were shown to be reversible. At the end of the 4-week recovery period, the histological changes in the penis had regressed.

Pregnancy, Nursing Mothers, and Pediatric Use

CAVERJECT is not indicated for use in pediatric patients or women.

Geriatric Use

A total of 341 subjects included in clinical studies were 65 and older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between elderly and younger patients, but decreased sensitivity of some older individuals cannot be ruled out.

CAVERJECT IMPULSE ADVERSE REACTIONS

Local Side Effects

The following local adverse reaction information was derived from controlled and uncontrolled studies of CAVERJECT Sterile Powder, including an uncontrolled 18-month safety study.

Penile Pain

Penile pain after intracavernosal administration of CAVERJECT was reported at least once by 37% of patients in clinical studies of up to 18 months in duration. 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. The frequency of penile pain was 2% in 294 patients who received 1 to 3 injections of placebo.

Prolonged Erection/Priapism

In clinical trials, prolonged erection was defined as an erection that lasted for 4 to 6 hours; priapism was defined as erection that lasted 6 hours or longer. The frequency of prolonged erection after intracavernosal administration of CAVERJECT was 4%, while the frequency of priapism was 0.4% (see WARNINGS).

Hematoma/Ecchymosis

The frequency of hematoma and ecchymosis was 3% and 2%, respectively. In most cases, hematoma/ecchymosis was judged to be a complication of a faulty injection technique. Accordingly, proper instruction of the patient in self-injection is of importance to minimize the potential of hematoma/ecchymosis (see DOSAGE AND ADMINISTRATION).

The following local adverse reactions were reported by fewer than 1% of patients after injection of CAVERJECT: balanitis, injection site hemorrhage, injection site inflammation, injection site itching, injection site swelling, injection site edema, urethral bleeding, penile warmth, numbness, yeast infection, irritation, sensitivity, phimosis, pruritus, erythema, venous leak, painful erection, and abnormal ejaculation.

Systemic Adverse Events

The following systemic adverse event information was derived from controlled and uncontrolled studies of CAVERJECT Sterile Powder, including an uncontrolled 18-month safety study.

The following systemic events, which were reported for < 1% of patients in clinical studies, were judged by investigators to be possibly related to use of CAVERJECT: testicular pain, scrotal disorder, scrotal edema, hematuria, testicular disorder, impaired urination, urinary frequency, urinary urgency, pelvic pain, hypotension, vasodilation, peripheral vascular disorder, supraventricular extrasystoles, vasovagal reactions, hypesthesia, non-generalized weakness, diaphoresis, rash, non-application site pruritus, skin neoplasm, nausea, dry mouth, increased serum creatinine, leg cramps, and mydriasis.

Hemodynamic changes, manifested as decreases in blood pressure and increases in pulse rate, were observed during clinical studies, principally at doses above 20 mcg and above 30 mcg of alprostadil, respectively, and appeared to be dose-dependent. However, these changes were usually clinically unimportant; only three patients discontinued the treatment because of symptomatic hypotension.

CAVERJECT had no clinically important effect on serum or urine laboratory tests.

The safety of CAVERJECT IMPULSE was evaluated in a study that compared the formulation of alprostadil for injection contained in CAVERJECT IMPULSE with the formulation contained in CAVERJECT Sterile Powder. The doses used by the 87 patients in this crossover study were the same for both formulations. The number and type of events reported for CAVERJECT IMPULSE were consistent between formulations in this study and in other controlled and uncontrolled studies with CAVERJECT Sterile Powder.

Post-Marketing Surveillance

The following additional adverse reactions have been reported: device malfunction/failure, drug ineffective and drug effect decreased.

OVERDOSAGE

Overdosage was not observed in clinical trials with CAVERJECT. If intracavernous overdose of CAVERJECT occurs, the patient should be under medical supervision until any systemic effects have resolved and/or until penile detumescence has occurred. Symptomatic treatment of any systemic symptoms would be appropriate.

CAVERJECT IMPULSE DOSAGE AND ADMINISTRATION

The dose of CAVERJECT should be individualized for each patient by careful titration under supervision by the physician. In clinical studies, patients were treated with CAVERJECT Sterile Powder in doses ranging from 0.2 to 140 mcg; however, since 99% of patients received doses of 60 mcg or less, doses of greater than 60 mcg are not recommended. In general, the lowest possible effective dose should always be employed. In clinical studies, over 80% of patients experienced an erection sufficient for sexual intercourse after intracavernosal injection of CAVERJECT.

Initial Titration in Physician's Office

Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology

Dosage titration should be initiated at 2.5 mcg of alprostadil. The 10 mcg strength of CAVERJECT IMPULSE is designed to allow delivery of a 2.5 mcg dose of alprostadil (see General Procedure for Solution Preparation). If there is a partial response at 2.5 mcg, the dose may be increased by 2.5 mcg to a dose of 5 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, doses in increments of 5 to 10 mcg may be given at least 24 hours apart until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. If there is no response to the initial 2.5-mcg dose, the second dose may be increased to 7.5 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, doses in increments of 5 to 10 mcg may be given at least 24 hours apart. The patient must stay in the physician's office until complete detumescence occurs.

Erectile Dysfunction of Pure Neurogenic Etiology (Spinal Cord Injury)

Dosage titration should be initiated at 1.25 mcg of alprostadil. Because CAVERJECT IMPULSE is designed to deliver doses of 2.5 mcg or greater (see General Procedure for Solution Preparation), CAVERJECT Sterile Powder may be used for an initial dose of 1.25 mcg. The initial dose may be increased by 1.25 mcg to a dose of 2.5 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, a dose of 5 mcg may be given during the next 24 hours. Thereafter, doses in increments of 5 mcg may be given at least 24 hours apart until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. The patient must stay in the physician's office until complete detumescence occurs.

The majority of patients (56%) in one clinical study involving 579 patients with erectile dysfunction of various etiologies were titrated to doses of greater than 5 mcg but less than or equal to 20 mcg. The mean dose at the end of the titration phase was 17.8 mcg of alprostadil.

Maintenance Therapy

The first injections of CAVERJECT must be done at the physician's office by medically trained personnel. Self-injection therapy by the patient should be started only after the patient is properly instructed and well trained in the self-injection technique. The physician should make a careful assessment of the patient's skills and competence with this procedure. The intracavernosal injection must be done under sterile conditions. The site of injection is usually along the dorso-lateral aspect of the proximal third of the penis. Visible veins should be avoided. The side of the penis that is injected and the site of injection must be alternated; the injection site must be cleansed with an alcohol swab.

The dose of CAVERJECT that is selected for self-injection treatment should provide the patient with an erection that is satisfactory for sexual intercourse and that is maintained for no longer than 1 hour. If the duration of erection is longer than 1 hour, the dose of CAVERJECT should be reduced. Self-injection therapy for use at home should be initiated at the dose that was determined in the physician's office; however, dose adjustment, if required (up to 57% of patients in one clinical study), should be made only after consultation with the physician. The dose should be adjusted in accordance with the titration guidelines described above. The effectiveness of CAVERJECT for long-term use of up to 6 months has been documented in an uncontrolled, self-injection study. The mean dose of CAVERJECT Sterile Powder at the end of 6 months was 20.7 mcg in this study. CAVERJECT IMPULSE in the 10 mcg strength is designed to deliver a minimum dose of 2.5 mcg and a maximum dose of 10 mcg. CAVERJECT IMPULSE in the 20 mcg strength is designed to deliver a minimum dose of 5 mcg and a maximum dose of 20 mcg. The physician should determine the most suitable formulation of CAVERJECT for the individual patient (CAVERJECT IMPULSE or CAVERJECT Sterile Powder).

Careful and continuous follow-up of the patient while in the self-injection program must be exercised. This is especially true for the initial self-injections, since adjustments in the dose of CAVERJECT may be needed. The recommended frequency of injection is no more than 3 times weekly, with at least 24 hours between each dose. All formulations of CAVERJECT are intended for single use only and should be discarded after use. The user should be instructed in the proper disposal of the injection materials (e.g., delivery system, needles).

While on self-injection treatment, it is recommended that the patient visit the prescribing physician's office every 3 months. At that time, the efficacy and safety of the therapy should be assessed, and the dose of CAVERJECT should be adjusted, if needed.

CAVERJECT as an Adjunct to the Diagnosis of Erectile Dysfunction

In the simplest diagnostic test for erectile dysfunction (pharmacologic testing), patients are monitored for the occurrence of an erection after an intracavernosal injection of CAVERJECT. Extensions of this testing are the use of CAVERJECT as an adjunct to laboratory investigations, such as duplex or Doppler imaging, ¹³³Xenon washout tests, radioisotope penogram, and penile arteriography, to allow visualization and assessment of penile vasculature. For any of these tests, a single dose of CAVERJECT that induces an erection with firm rigidity should be used.

General Procedure for Solution Preparation

CAVERJECT IMPULSE consists of a disposable, single-dose, dual chamber syringe system. The system includes a glass cartridge, which contains sterile, freeze-dried alprostadil in the front chamber and sterile bacteriostatic water for injection in the rear chamber. Following proper reconstitution instructions, the 10 mcg strength syringe can deliver up to 0.5 mL of solution. Each 0.5 mL of solution contains 10 mcg of alprostadil, 324.7 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol. The delivery system can be set to deliver a solution volume of 0.125, 0.25, 0.375, or 0.50 mL to enable administration of 2.5, 5, 7.5, or 10 mcg of alprostadil. Following proper reconstitution instructions, the 20 mcg strength syringe can deliver up to 0.5 mL of solution. Each 0.5 mL of solution contains 20 mcg of alprostadil, 649.3 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol. The delivery system can be set to deliver a solution volume of 0.125, 0.25, 0.375, or 0.50 mL to enable administration of 5, 10, 15, or 20 mcg of alprostadil. After reconstitution, the solution of CAVERJECT should be used within 24 hours when stored at or below 25°C (77°F). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The product should not be used if particulate matter or discoloration are present. Following a single use, the injection delivery system and any remaining solution should be properly discarded.

Caution

CAVERJECT IMPULSE is for single use only. Do not use any remaining CAVERJECT solution.

HOW SUPPLIED

CAVERJECT IMPULSE is supplied as a disposable, single-dose, dual chamber syringe system. The system includes a glass cartridge, which contains sterile, freeze-dried alprostadil in the front chamber and sterile bacteriostatic water for reconstitution in the rear chamber. The syringes contain either 12.8 or 25.6 mcg of alprostadil to allow delivery of a maximum of 10 or 20 mcg/0.5mL. Store the unreconstituted product at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

When reconstituted and used as directed, the deliverable amount for the 10 mcg strength is 10 mcg/0.5 mL or an increment of 10 mcg/0.5 mL, 2.5 mcg/0.125 mL, 5 mcg/0.25 mL, or 7.5 mcg/0.375 mL of alprostadil and the deliverable amount for the 20 microgram strength is 20 mcg/0.5 mL or an increment of 20 mcg/0.5 mL, 5 mcg/ 0.125 mL, 10 mcg/0.250 mL, or 15 mcg/0.375 mL of alprostadil. The reconstituted solution should be used within 24 hours when stored at or below 25°C (77°F).

CAVERJECT IMPULSE is supplied in a carton containing 2 blister trays. Each blister tray contains one dual chamber syringe system, one needle and 2 alcohol swabs. It is available in the following strengths:

CAVERJECT is also available as follows:

CAVERJECT Sterile Powder (alprostadil for injection) packaged in vials, 6 vials per carton

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Rx only

LAB- 0007-4.0
December 2013

Patient Instructions For:

CaverJect Impulse^®
Dual Chamber System
alprostadil for injection

Read this information carefully before using CAVERJECT [KAV-er-jeckt]. Read the information you get each time you renew your prescription, in case anything has changed. This is a summary and does not replace talking with your doctor when you start this medication and at check-ups. If you have any questions or concerns, talk to your doctor about them.

What is CAVERJECT?

CAVERJECT is a medicine to treat male impotence (erectile dysfunction). CAVERJECT is injected into a specific area of the penis and should produce an erection in 5 to 20 minutes. The erection should last for no longer than 1 hour.

CAVERJECT IMPULSE is for one use only and should be thrown away properly after a single use.

CAVERJECT does not protect you from sexually transmitted diseases (STDs), such as HIV (the virus that causes AIDS). In addition, small amounts of bleeding at the injection site can increase the risk of passing diseases carried by the blood, such as HIV.

What are the causes of and treatments for impotence?

There are several causes of impotence. These include medications that you may be taking for other conditions, poor blood circulation in the penis, nerve damage, emotional problems, too much smoking or alcohol use, use of street drugs, and hormonal problems. Often, impotence is due to more than one cause.

Treatments for impotence include switching medications if you are taking a medication that causes impotence, prescription medications, medical devices that produce an erection, surgical procedures to correct blood flow in the penis, penile implants, and psychological counseling.

You should not stop taking any prescription medications, unless told to do so by your doctor.

The use of other medical treatments for impotence in combination with CAVERJECT is not recommended. Discuss any concerns you may have about combination treatment with your doctor.

Who should not use CAVERJECT?

Do not use CAVERJECT if you have certain conditions that might cause long-lasting erections (lasting more than 4 hours). Long-lasting erections may cause penis damage. These conditions include:

• sickle cell anemia or trait
• leukemia
• tumor of the bone marrow (multiple myeloma)

Do not use CAVERJECT if you

• have a penile implant
• have an abnormally formed penis
• have other penis problems
• were told by your doctor not to have sex

Women and children should not use CAVERJECT.

How should I use CAVERJECT?

You will be treated with CAVERJECT in your doctor's office to find out what dose is best for you. After that, you can inject it yourself at home. Do not use it more than 3 times a week. There should be at least 24 hours between doses. See your doctor for regular check-ups to be sure CAVERJECT is not causing damage and that it is working as well as possible.

See the section "Instructions for Use" at the end of this leaflet for details about how to use CAVERJECT.

What are the possible side effects of CAVERJECT?

About 4 in 100 men who use CAVERJECT may get erections that last more than 4 hours. These can cause serious and permanent damage. Call your doctor or seek professional help immediately if you still have an erection 4 hours after injection.

The most common side effect of CAVERJECT is mild to moderate pain after injection. About one-third of patients report this effect.

You may get a small amount of bleeding at the injection site. This is more likely if you have a medical condition or are taking a medicine that interferes with blood clotting.

Call your doctor if you notice any redness, lumps, swelling, tenderness, or curving of the erect penis. Also, tell your doctor about any penis pain you did not have before or other penis problems you have.

There is a possibility of needle breakage with use of CAVERJECT IMPULSE. To best avoid breaking the needle, you should pay careful attention to your doctor's instructions and try to handle the syringe and needle properly. If the needle breaks during injection and you are able to see and grasp the broken end, you should remove it and contact your doctor. If you cannot see or cannot grasp the broken end, you should promptly contact your doctor.

How should I store CAVERJECT IMPULSE?

• Unmixed packages of CAVERJECT IMPULSE should be stored at room temperature. Temperatures between 59° to 86°F (15° to 30°C) are allowed. Avoid storing CAVERJECT IMPULSE at very high and very low temperatures.
• During travel, do not let the medicine freeze or be stored at a temperature above 77°F (25°C). For example, do not store it in checked luggage during air travel or leave it in a closed automobile.
• After mixing, CAVERJECT IMPULSE should be used within 24 hours. It should be kept at a temperature of 77°F or below during this storage time.

General advice about prescription medicines

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have any concerns about CAVERJECT, ask your doctor. Your doctor or pharmacist can give you information about CAVERJECT that was written for health care professionals. Do not use CAVERJECT for a condition for which it was not prescribed. Do not share CAVERJECT with other people.

You can get more information about impotence (erectile dysfunction) and its treatment from the National Institutes of Health (Washington, DC), the American Foundation for Urological Diseases (Baltimore, MD), or the Impotence Institute of America (Washington, DC).

INSTRUCTIONS FOR USE

Before you use CAVERJECT, your doctor must train you in how to prepare and give the injection properly.

Before using CAVERJECT, talk to your doctor about what to expect when using it, possible side effects, and what to do if side effects occur. Your dose has been selected for your individual needs. Do not change your dose without consulting your doctor. If you are not sure of the volume or dose to be used, talk to your doctor or pharmacist.

Follow these instructions exactly to properly prepare the syringe for use, and to correctly inject a sterile (germ-free) dose of CAVERJECT.

Supplies Needed

The CAVERJECT IMPULSE carton contains two (2) sealed plastic trays, with one dose of Caverject in each tray.

Each tray contains: (a) a syringe, (b) a separate needle assembly and (c) two alcohol swabs. The syringe and the needle assembly are shown in Figure A (below). Please note that the needle assembly is packaged as a single piece and is sealed with a paper cover on the bottom.

DO NOT try to assemble the syringe until you have read ALL of the instructions.

First-read through ALL of the instructions (Step 1 through Step 12) before trying to assemble the syringe. Then go back to Step 1 and begin to prepare the syringe for use.

CAVERJECT IMPULSE is available in two versions: the 10 mcg strength (white plunger) and the 20 mcg strength (blue plunger). Each syringe is designed to be used only one time, but you can select the dose that will be delivered:

• The 10 mcg strength syringe (white plunger) can deliver 10 mcg (the full dose), or one of three partial doses: 7.5 mcg, or 5 mcg, or 2.5 mcg.
• The 20 mcg strength syringe (blue plunger) can deliver 20 mcg (the full dose), or one of three partial doses: 15 mcg, or 10 mcg, or 5 mcg.

If you deliver a partial dose there will be left-over solution in the syringe – this is normal.

MAKE SURE YOU HAVE THE CORRECT STRENGTH OF CAVERJECT IMPULSE to deliver your assigned dose

INSTRUCTIONS for PREPARING the SYRINGE (Step 1 through Step 12)

	Wash your hands thoroughly and dry them with a clean towel.
STEP 1.	Open the sealed plastic tray. Remove the syringe, the needle assembly, and the alcohol swabs from the tray. All items should be present.
	Look at the needle assembly. The needle assembly is a sealed unit that contains the outer protective cap, the inner protective cap, and the superfine needle, as shown in Figure A. It is sealed with a small round paper cover (not shown in Figure A).
	Do not open the needle assembly at this point – leave it sealed inside the outer protective cap.
	Next, examine the syringe. Find the location of the dose window. Right now you will not see anything in this window, but at a later Step, a number will appear in this window (the dose to be delivered).
	Finally, look at the Plunger, but do not move it at this time. During the assembly process, some Steps may ask you to ROTATE the plunger and other steps may ask you to PUSH the plunger.
	It is important to only rotate the plunger – or only push – as directed in each Step, but DO NOT do both at the same time.

Never PUSH on the plunger – even slightly – while trying to rotate it. This can cause the plastic threads on the plunger rod to stick.

	STEP 2.	Open the packet containing the alcohol swab, and then pick up the syringe. Use the alcohol swab to wipe the rubber membrane at the tip of the syringe (Figure B). Discard the alcohol swab.
	STEP 3.	Pick up the Needle Assembly. Grab the paper tab and peel off the paper cover (lid) from the bottom of the needle assembly (Figure C).
	STEP 4.	Hold the needle assembly by the cap. Pick up the syringe with your other hand. Press the needle assembly onto the tip of the syringe and turn it clockwise (like tightening a screw) until the needle assembly is firmly locked into place. Remove (twist off - clockwise) the outer protective cap from the needle (Figure D), but DO NOT REMOVE the inner protective cap at this time. The inner protective cap is the thin plastic tube that directly covers the needle. It will be removed later. If you are not sure which piece is the inner protective cap, see Figure A (Step 1) to identify the inner protective cap.
	STEP 5.	The next few steps will mix the powder and the fluid to make the Caverject Impulse solution. 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, as shown in Figure E.
	STEP 6.	Slowly ROTATE the plunger rod clockwise (like tightening a screw,) until it goes all the way in and stops (Figure F). This automatically combines the drug powder and the fluid.
			DO NOT turn the plunger rod counter-clockwise (do not try to "unscrew" the plunger rod).
			DO NOT PUSH on the plunger while trying to rotate it. This can cause the plastic threads on the plunger rod to stick.
	STEP 7.	Turn the syringe upside down several times to make sure the solution is evenly mixed. The solution should be clear. Do not use it if it is cloudy or contains particles.
	STEP 8. STEP 9.	Hold the syringe with the needle upward and carefully remove the inner protective cap from the needle (Figure G). Do not touch the exposed needle because it is sterile. Next, you need to remove any large bubbles from the solution. Lightly tap the glass cartridge a few times with your finger until any large bubbles disappear up into the tip. Very small bubbles may remain.
	STEP 10.	With the syringe pointed upward (Figure H), use your thumb to push in the plunger rod until it stops. This will push the air out. Some liquid will appear at the needle point. After pressing the plunger you may still see some small bubbles on the wall of the glass cartridge. This is normal.
			If you can't press the plunger rod in, check that the plunger rod is rotated all the way: turn it clockwise until it stops, and then repeat Step 10.
			After the plunger is pushed in – Do Not rotate the plunger. That will be done in the next step.
	STEP 11.	PLEASE READ the following before going on. In Step 11, you will need to set the dose by ROTATING the plunger until the correct dose appears in the small oval Dose Window on the syringe. The plunger must be rotated "clock-wise" – like tightening a screw.
			DO NOT PUSH on the plunger while trying to rotate it. This can cause the plastic threads on the plunger rod to stick. If the plunger does stick, you can try to free it by gently turning it backward ("unscrewing it") and trying again.
		TO SET THE DOSE: Locate the Dose Window on the syringe. This small oval window (above the left thumb in Figure I) is where the dose number will appear when the plunger is rotated. Then – holding the syringe as shown in Figure I, slowly turn the plunger rod clockwise (like tightening a screw – see arrow in Figure I) until the correct dose number appears in the center of the window (Figure J). 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

STEP 12.

The syringe is now ready for use. Set the syringe down on a flat level surface. The needle is sterile .Make sure the needle does not touch the surface or anything else.

How to give the injection

• Make yourself comfortable. Take some time to relax yourself and your partner. If your doctor has recommended you use an alcohol cleansing swab, open one now.
• Make sure that the needle is not bent. If it is, do not use it. Do not attempt to straighten the needle out. Properly discard it.

The injection will go into the part of the penis shown as the shaded area in Figure K. Do not inject into the white areas because there may be blood vessels in the white areas. Also see Figure L.The correct injection angle is shown in Figure L.

If your doctor has recommended that you use an alcohol swab, wipe over the area for injection and let it dry. Reconfirm that the correct dose is visible in the dose window. If the correct dose is not in the dose window, repeat Step 11.Take hold of the penis from the front, with the first two fingers underneath close to the testicles and the thumb on top (Figure M).

Gently squeeze the penis between your thumb and finger so that the injection site bulges out. If there is a foreskin on the penis, make sure it is stretched.

Keeping a firm grip on the penis and taking the syringe in your free hand, push the needle straight through the skin all the way into the bulgy part (corpora cavernosa). Avoid veins or other obvious blood vessels (Figures K and L).

Push the plunger firmly and steadily until it no longer moves. Plunger movement may be very small or undetectable if administering a partial dose.

If the plunger does not move easily adjust the needle depth slightly and try again. Do not force the solution from the syringe.

After completing the injection, carefully pull the needle out. A drop of liquid may remain on the tip of the needle. Press gently on the injection site with the alcohol swab. Massage the penis to help the Caverject Impulse solution spread through it.

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•   Some liquid will remain in the syringe if you delivered a PARTIAL dose. This is expected. Do not try to inject left-over liquid from a partial dose. Syringes used to inject a partial dose must be discarded since each syringe can only be used one time. Discard syringes with left-over liquid.
  
  
  • A partial dose is 5 mcg, 10 mcg or 15 mcg for the BLUE plunger syringe.
  • A partial dose is 2.5 mcg, 5 mcg, or 7.5 mcg for the WHITE plunger syringe.

Do not keep any solution in the cartridge to use for a second injection. When you have finished with the syringe, discard it carefully as recommended by your doctor, so no one will use it or stick themselves with it.

How often can you use Caverject Impulse?

Do not use Caverject Impulse more than once in 24 hours or more than three times in a week. Change the exact place and side of the penis that you inject Caverject Impulse each time you use it.

Your erection after injecting Caverject Impulse

It will take a little while for your erection to occur after the injection. With the correct dose of Caverject Impulse your erection should be sufficiently firm enough for you and your partner to engage in sexual intercourse. Usually, your erection should not last longer than an hour. If you would like it to last longer, talk to your doctor. If your erection lasts longer than four hours, you should seek medical assistance immediately (see section on side effects below).

If you use too much Caverject Impulse

Tell your doctor immediately as you may need treatment; particularly if you experience an erection that lasts for longer than four hours.

If you have any further questions on how to use this product, ask your doctor.

Disposal of Injection Materials

After use, dispose of all injection materials safely. Your pharmacist may be able to supply a disposal box especially for disposable injection delivery systems. As with all prescription medicines, do not allow anyone else to use your medicine.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Rx only

LAB-0641-1.0
December 2013

PRINCIPAL DISPLAY PANEL - 10 microgram Syringe Label

NDC 63539-121-10

Caverject Impulse^®
Dual Chamber System
alprostadil for injection

10 micrograms

KEEP OUT OF REACH OF CHILDREN
PROFESSIONAL SAMPLE - NOT FOR SALE

U.S. Pharmaceuticals
Pfizer Inc, NY, NY 10017 - MADE IN BELGIUM

8Q4727

LOT/EXP

PRINCIPAL DISPLAY PANEL - 10 microgram Syringe Carton

Pfizer

Caverject Impulse^®

alprostadil for injection

10 micrograms

NDC 63539-121-11
Contains 2 of NDC 63539-121-10

For intracavernosal use only
Dual Chamber System

Contains 2 single dose injection systems
Diluent Contains Benzyl Alcohol

PROFESSIONAL SAMPLE - NOT FOR SALE

Rx only

PRINCIPAL DISPLAY PANEL - 20 microgram Syringe Label

NDC 63539-221-20

Caverject Impulse^®
Dual Chamber System
alprostadil for injection

20 micrograms

KEEP OUT OF REACH OF CHILDREN
PROFESSIONAL SAMPLE - NOT FOR SALE

U.S. Pharmaceuticals
Pfizer Inc, NY, NY 10017 - MADE IN BELGIUM

8Q4728

LOT/EXP

PRINCIPAL DISPLAY PANEL - 20 microgram Syringe Carton

Pfizer

Caverject Impulse^®

alprostadil for injection

20 micrograms

NDC 63539-221-21
Contains 2 of NDC 63539-221-20

For intracavernosal use only
Dual Chamber System

Contains 2 single dose injection systems
Diluent Contains Benzyl Alcohol

PROFESSIONAL SAMPLE - NOT FOR SALE

Rx only

Caverject Impulse Alprostadil INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION Product Information Product Type Human prescription drug label Item Code (Source) NDC:63539-121 Route of Administration INTRACAVERNOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPROSTADIL ALPROSTADIL 10 ug Inactive Ingredients Ingredient Name Strength ALFADEX LACTOSE SODIUM CITRATE BENZYL ALCOHOL HYDROCHLORIC ACID SODIUM HYDROXIDE water Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63539-121-10 0.5 in 1 SYRINGE 2 NDC:63539-121-11 2 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021212 2014-05-04

Caverject Impulse Alprostadil INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION Product Information Product Type Human prescription drug label Item Code (Source) NDC:63539-221 Route of Administration INTRACAVERNOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPROSTADIL ALPROSTADIL 20 ug Inactive Ingredients Ingredient Name Strength ALFADEX LACTOSE SODIUM CITRATE BENZYL ALCOHOL HYDROCHLORIC ACID SODIUM HYDROXIDE water Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63539-221-20 0.5 in 1 SYRINGE 2 NDC:63539-221-21 2 in 1 CARTON Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021212 2014-05-04