Caverject - alprostadil.pdf - Poradniki seksualne - SirPozamiatane

Caverject ®

alprostadil for injection

For Intracavernosal Use

DESCRIPTION

CAVERJECT Sterile Powder contains alprostadil as the naturally occurring form of

prostaglandin E 1 (PGE 1 ) and is designated chemically as (11α,13E,15S)-11,15-

dihydroxy-9-oxoprost-13-en-1-oic acid. The molecular weight is 354.49.

Alprostadil is a white to off-white crystalline powder with a melting point between 115°

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:

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 2α 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 cellswas 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, 13,14-

dihydro-15-oxo-PGE 1 , 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 intravenousadministration.

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.

INDICATION AND USAGE

CAVERJECT is indicated for the treatment of erectile dysfunction due to neurogenic,

vasculogenic, psychogenic, or mixed etiology.

Intracavernosal CAVERJECT may be a useful adjunct to other diagnostic tests in the

diagnosis of erectile dysfunction.

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 should not be used in women or children and is not for use in newborns.

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

contraindicated.

PRECAUTIONS

General Precautions: Prolonged erection (erection lasting 4 to 6 hours) and priapism

(erection lasting over 6 hours) are known to occur following intracavernosal

administration of vasoactive substances, including CAVERJECT. The patient should 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. Treatment of

priapism should be according to established medical practice.

The overall incidence of penile fibrosis, including Peyronie’s disease, 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 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.

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.

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. The instructions for preparation of the solution of CAVERJECT

should be carefully followed. Vials with precipitates or discoloration should be discarded.

The reconstituted vial is designed for one use only and should be discarded after

withdrawal of proper volume of the solution. The content of the reconstituted vial should

not be shaken. The needle must be properly discarded after use; it must not be re-used or

shared with other persons. Patient instructions for administration are included in each

package of CAVERJECT.

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 intravenous 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 checkups 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 milligram/kilogram/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 micrograms of

alprostadil per injection. An additional two groups of 6 monkeys each were injected with

vehicle or with 8.25 micrograms/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

Caverject - alprostadil.pdf

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