Alprostadil Injection

Name: Alprostadil Injection

Description

CAVERJECT Sterile Powder contains alprostadil as the naturally occurring form of prostaglandin E1 (PGE1) and is designated chemically as (11α,13E,15S)-11,15dihydroxy-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 per 100 milliliter double distilled water. CAVERJECT is available as a sterile freeze-dried powder for intracavernosal use in four sizes: 5, 10, 20 and 40 micrograms per vial — When reconstituted as directed with 1 milliliter of bacteriostatic water for injection or sterile water, both preserved with benzyl alcohol 0.945% w/v, gives 1.13 milliliters of reconstituted solution. Each milliliter of CAVERJECT contains 5.4, 10.5, 20.5 or 41.1 micrograms of alprostadil depending on vial strength, 172 milligrams of lactose, 47 micrograms of sodium citrate and 8.4 milligrams of benzyl alcohol. The deliverable amount of alprostadil is 5, 10, 20 or 40 micrograms per milliliter because approximately 0.4 microgram for the 5 microgram strength, 0.5 microgram for the 10 and 20 microgram strengths and 1.1 microgram for the 40 microgram strength is lost due to adsorption to the vial and syringe. When necessary, 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:

Side effects

Local Adverse Reactions

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

Local Adverse Reactions Reported by ≥ 1% of Patients Treated with CAVERJECT for up to 18 Months*

Event N = 1861
Penile pain 37%
Prolonged erection 4%
Penile fibrosis** 3%
Injection site hematoma 3%
Penis disorder*** 3%
Injection site ecchymosis 2%
Penile rash 1%
Penile edema 1%
*Except for penile pain (2%), no significant local adverse reactions were reported by 294 patients who received 1 to 3 injections of placebo.
** See General Precautions.
*** Includes numbness, yeast infection, irritation, sensitivity, phimosis, pruritus, erythema, venous leak, penile skin tear, strange feeling of penis, discoloration of penile head, itch at tip of penis.

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%. In the majority of cases, spontaneous detumescence occurred. To minimize the chances of prolonged erection or priapism, CAVERJECT should be titrated slowly to the lowest effective dose (see DOSAGE AND ADMINISTRATION section). The patient must be instructed to immediately report to his physician or, if unavailable, to seek immediate medical assistance for any erection that persists for longer than 4 hours. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

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, including an uncontrolled 18-month safety study.

Systemic Adverse Events Reported by ≥ 1% of Patients Treated with CAVERJECT for up to 18 Months*

Body System/Reaction CAVERJECT
N = 1861
Cardiovascular System
  Hypertension 2%
Central Nervous System
  Headache 2%
  Dizziness 1%
Musculoskeletal System
  Back pain 1%
Respiratory System
  Upper respiratory infection 4%
  Flu syndrome 2%
  Sinusitis 2%
  Nasal congestion 1%
  Cough 1%
Urogenital System
  Prostatic Disorder** 2%
Miscellaneous
  Localized pain*** 2%
  Trauma**** 2%
*No significant adverse events were reported by 294 patients who received 1 to 3 injections of placebo.
** prostatitis, pain, hypertrophy, enlargement
*** pain in various anatomical structures other than injection site
**** injuries, fractures, abrasions, lacerations, dislocations

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 micrograms and above 30 micrograms 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.

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 PGF2α 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 micrograms alprostadil, mean peripheral plasma concentrations of alprostadil at 30 and 60 minutes after injection (89 and 102 picograms/milliliter, respectively) were not significantly greater than baseline levels of endogenous alprostadil (96 picograms/milliliter). Alprostadil is bound in plasma primarily to albumin (81% bound) and to a lesser extent α-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 micrograms alprostadil, peripheral levels of the major circulating metabolite, 13,14dihydro-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/milliliter. 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 on the pharmacokinetics of alprostadil has not been formally evaluated.

Renal And Hepatic Insufficiency

The pharmacokinetics of alprostadil have not been formally examined 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.

What are some things I need to know or do while I take Alprostadil Injection?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how alprostadil injection affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Talk with your doctor before you drink alcohol.
  • This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
  • This medicine is not approved for use in women.
  • There is a chance of the needle breaking when using the injection. Needles have broken with part of the needle still in the penis. If the needle breaks and you can grab the broken end, take it out and call your doctor. If you cannot grab the broken end, call your doctor right away.
  • This medicine has benzyl alcohol in it. Benzyl alcohol may cause very bad and sometimes deadly side effects in newborns or infants. This medicine is not approved for use in children. Talk with the doctor.

How do I store and/or throw out Alprostadil Injection?

  • Store as you have been told by the doctor.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

What is alprostadil (caverject, caverject impulse, edex, muse)?

Alprostadil is used to treat erectile dysfunction (impotence) and to help diagnose certain causes of this disorder. Alprostadil is also used to improve blood flow in newborn babies with a certain genetic heart condition. This alprostadil medication guide addresses only the adult male use of this medication in erectile disorders.

Alprostadil relaxes blood vessels and muscles in the penis. This increases blood flow into the penis, causing an erection.

Alprostadil may also be used for purposes not listed in this medication guide.

What is the most important information i should know about alprostadil (caverject, caverject impulse, edex, muse)?

Alprostadil is used to treat erectile dysfunction (impotence) and to help diagnose certain causes of this disorder. Alprostadil is also used to improve blood flow in newborn babies with a certain genetic heart condition. This alprostadil medication guide addresses only the adult male use of this medication in erectile disorders.

You should not use this medication if you are allergic to alprostadil, or if you have sickle cell anemia, leukemia, a bone marrow tumor, a curved or deformed penis, penile fibrosis or Peyronie's disease, a penile implant, or if you have been told you should not have sexual intercourse for health reasons.

Before using alprostadil, tell your doctor if you have heart disease, high blood pressure, a bleeding disorder, a history of blood clots, or a disease that could be passed in blood (such as hepatitis or HIV).

The injectable form of alprostadil is injected into the side of the penis. The transurethral pellet is a very small suppository that is inserted into the opening of the penis (the urethra).

Use this medication exactly as it was prescribed for you. Using too much alprostadil can be very dangerous. The medicine comes with patient instructions for safe and effective use. Follow these directions carefully.

Your first dose of this medicine will be given in your doctor's office so you can be observed for how well the medication works and if it causes any side effects.

Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes. Call your doctor, nurse, or pharmacist if you have any questions. Using an alprostadil transurethral pellet improperly could cause damage to your urethra.

Alprostadil is used only when needed to get an erection. An erection should occur within 5 to 20 minutes after you use the medication, and should last for 30 to 60 minutes.

Seek emergency medical attention if you have a painful or prolonged erection lasting 4 hours or longer.

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