Caverject

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Alprostadil 6.15 µg equivalent to 5 µg/ml after reconstitution.
Available from:
Pharmacia Limited Company trading as Pharmacia
INN (International Name):
Alprostadil 6.15 µg (=5 µg/ml after reconstitution.)
Dosage:
5 mcg
Pharmaceutical form:
Powder for injection
Composition:
Active: Alprostadil 6.15 µg equivalent to 5 µg/ml after reconstitution. Excipient: Hydrochloric acid Lactose monohydrate Sodium citrate dihydrate Sodium hydroxide Benzyl alcohol Water for injection
Units in package:
Combination pack, 6x(vial+ diluent syringe),
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Pharmacia & Upjohn Company LLC
Product summary:
Package - Contents - Shelf Life: Combination pack, 6x(vial+ diluent syringe) -   - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) 48 hours reconstituted stored at or below 25°C 7 days reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) 24 months from date of manufacture stored at or below 25°C 24 hours reconstituted (not refrigerated) stored at or below 25°C - Combination pack, 1x(vial+ diluent syringe) - 1 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) 48 hours reconstituted stored at or below 25°C 7 days reconstituted stored at 2° to 8°C (Refrigerate, do not freeze) 24 months from date of manufacture stored at or below 25°C 24 hours reconstituted (not refrigerated) stored at or below 25°C - Syringe, glass, 1x1ml - 1 mL - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) - Vial, glass, 1x5?g - 5 ?g - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze)
Authorization number:
TT50-3370/1
Authorization date:
1993-02-16

DATA SHEET

CAVERJECT

®

Alprostadil

10 micrograms and 20 micrograms Powder for Injection

PRESENTATION

Caverject

white

crystalline

powder

containing

10 micrograms

20 micrograms

alprostadil in a 5 mL clear glass vial.

USES

Actions

Alprostadil is the naturally occurring form of prostaglandin E

(PGE

). 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

in vitro

. In pigtail monkeys

Macaca nemestrina

), alprostadil increased cavernous arterial blood flow

in vivo.

The degree

duration

cavernous

smooth

muscle

relaxation

this

animal

model

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/mL,

respectively) were not significantly greater than baseline levels of endogenous alprostadil

(96 picograms/mL). Alprostadil is bound in plasma primarily to albumin (81% bound) and to

a lesser extent

-globulin IV-4 fraction (55% bound). No significant binding to erythrocytes

or white blood cells was observed.

Biotransformation or Metabolism

Alprostadil

rapidly

converted to

compounds

which

further

metabolised

prior

excretion.

Following

intravenous

administration,

approximately

circulating

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alprostadil is metabolised 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 metabolised. The primary metabolites of alprostadil are 15-keto-

, 15-keto-13,14-dihydro-PGE

, and 13,14-dihydro-PGE

. In contrast to 15-keto-PGE

and 15-keto-13,14-dihydro-PGE

, which lack almost completely biological activity, 13,14-

dihydro-PGE

has been shown to lower blood pressure and inhibit platelet aggregation.

Following intravenous or intra-arterial administration of alprostadil, levels of this metabolite

were in the same order of magnitude as those of PGE

, while levels of 15-keto-13,14-

dihydro-PGE

, the major circulating metabolite, were more than 10-fold higher. Plasma 15-

keto-PGE

remained

undetectable

throughout

observation

period.

Following

intracavernosal

injection

20 micorgrams

alprostadil,

peripheral

levels

major

circulating metabolite, 13,14-dihydro-15-oxo-PGE

, increased to reach a peak 30 minutes

after injection and returned to pre-dose levels by 60 minutes after injection while peripheral

levels

alprostadil

were

significantly

greater

than

baseline

levels

.

Plasma

concentrations of 13,14-dihydro-PGE

were not determined.

Elimination

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 faeces. There is no evidence of tissue retention of alprostadil or its

metabolites following intravenous administration. In healthy men, 70% to 90% of alprostadil

is extensively extracted and metabolised in a single pass through the lungs resulting in a

metabolic half-life of less than one minute

.

Effect on Race

The potential effect of race on the pharmacokinetics of alprostadil following intracavernous

use has not been evaluated.

Use in the Elderly

The potential effect of age on the pharmacokinetics of alprostadil following intracavernous

use has not been evaluated.

Use in the Renal Disease

Pulmonary first-pass metabolism is the primary factor influencing the systemic clearance of

alprostadil. Although the pharmacokinetics of alprostadil have not been formally examined

in patients with renal insufficiency, alterations in renal function would not be expected to

have a major influence on the pharmacokinetics of alprostadil.

Use in Hepatic Disease

Pulmonary first-pass metabolism is the primary factor influencing the systemic clearance of

alprostadil. Although the pharmacokinetics of alprostadil have not been formally examined

in patients with hepatic insufficiency, alterations in hepatic function would not be expected to

have a major influence on the pharmacokinetics of alprostadil.

INDICATIONS

Caverject is indicated for the treatment of erectile dysfunction.

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Caverject may be a useful adjunct to other diagnostic tests in the diagnosis of erectile

dysfunction.

DOSAGE AND ADMINISTRATION

General Information

Caverject is administered by direct intracavernosal injection. A 13 mm, 27 to 30 gauge,

needle is recommended. The dose of Caverject should be individualised by careful titration

under a physician’s supervision.

The first injections of Caverject must be done at the physician's office by medically trained

personnel. Self-injection therapy by the patient can 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 either dorso-lateral aspect of the proximal third of the penis. Visible veins

should be avoided. Alternate which side of the penis is injected and vary the site of injection

Reconstituted solutions of Caverject are intended for single use only; discard after use.

Instruct the user in the proper disposal of the syringe, needles, and vial.

Initial Titration in Physician's Office

During

dose

titration,

patient

must

stay

physician's

office

until

complete

detumescence occurs. If there is no response, the next higher dose may be given within one

hour. If there is a response, allow at least a one-day interval before administering the next

dose.

Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology

Dosage titration should be initiated at 2.5 micrograms of alprostadil. If there is a partial

response, the dose may be increased by 2.5 micrograms to a dose of 5 micrograms and then

in increments of 5 to 10 micrograms, depending upon erectile response, until the dose that

produces an erection suitable for intercourse and not exceeding a duration of one hour is

reached. If there is no response to the initial 2.5 microgram dose, the second dose may be

increased to 7.5 micrograms, followed by increments of 5 to 10 micrograms.

Erectile Dysfunction of Pure Neurogenic Etiology (Spinal Cord Injury)

Dosage titration should be initiated at 1.25 micrograms of alprostadil. The dose may be

increased by 1.25 micrograms to a dose of 2.5 micrograms, followed by an increment of

2.5 micrograms to a dose of 5 micrograms, and then in 5 microgram increments until the dose

that produces an erection suitable for intercourse and not exceeding a duration of one hour is

reached.

Maintenance Therapy: Self-Injection

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 one hour. If the duration of erection is longer than one 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, if dose adjustment is required, it should be

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done only after consultation with the physician. The dose should be adjusted in accordance

with the titration guidelines described above. The lowest effective dose should be employed.

The recommended frequency of injection is no more than three times weekly with at least 24

hours between each dose. The patient may expect an erection to develop within 5 to 20

minutes.

The effectiveness of Caverject for long-term use of up to six months has been documented in

an uncontrolled, self-injection study. The mean dose of alprostadil at the end of six months

20.7 micrograms.

majority

patients,

maintenance

dose

between

5 micrograms and 20 micrograms. Maintenance doses of greater than 60 micrograms are not

recommended.

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

this

testing

include

Caverject

adjunct

laboratory

investigations, such as duplex or Doppler imaging,

Xenon washout tests, radioisotope

penogram,

penile

arteriography,

allow

visualisation

assessment

penile

vasculature. For any of these tests, a single dose of Caverject that induces an erection with

firm rigidity should be used.

Treatment Monitoring Recommendations

Regular follow-up is indicated while the patient is in the self-injection program. This is

especially true for the initial self-injections, since adjustments in the dose of Caverject may

be needed.

Instructions to Patients

Caverject uses a superfine 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, required hospitalisation and

surgical removal. Careful patient instruction in proper handling and injection techniques may

minimise the potential for needle breakage. The patient should be instructed that, if the

needle is bent, it must not be used; and no attempt should be made to straighten a bent needle.

A bent needle should be removed from the syringe and discarded and a new, unused, sterile

needle attached to the syringe.

CONTRAINDICATIONS

Caverject is contraindicated in the following patients:

patients who have a known hypersensitivity to alprostadil or any component of Caverject

patients who have conditions that might predispose them to priapism, such as sickle cell

anaemia or trait, multiple myeloma, or leukaemia

patients

with

anatomical

deformation

penis,

such

angulation,

cavernosal

fibrosis, or Peyronie's disease

patients with penile implants

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patients for whom sexual activity is inadvisable or contraindicated

women

children and newborns (see

Warnings and Precautions

WARNINGS AND PRECAUTIONS

Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated

prior to initiation of therapy with Caverject.

Priapism (erection lasting over six hours) may occur following intracavernosal administration

of Caverject. To minimise the risk select the lowest effective dose and instruct patients to

immediately consult with their physician and seek medical assistance for any prolonged

erection lasting more than 4 hours. Treatment of priapism should be according to established

medical practice.

Penile fibrosis, including angulation, fibrotic nodules, and Peyronie's disease, may occur

following the intracavernosal administration of Caverject. The occurrence of fibrosis may

increase with increased duration of use of Caverject. Regularly scheduled follow-up and

examination of the penis to detect signs of penile fibrosis or Peyronie's disease is strongly

recommended. Treatment with Caverject should be discontinued in patients who develop

penile angulation, cavernosal fibrosis, or Peyronie's disease.

Because a small amount of bleeding may occur at the injection site patients should be

counselled about the protective measures that are necessary to guard against the spread of

sexually

transmitted

diseases,

including

HIV,

blood-borne

diseases.

Patients

anticoagulants, such as warfarin or heparin, may have increased propensity for bleeding after

intracavernosal injection.

The possibility of needle breakage exists with Caverject, and careful patient instruction in

proper handling and injection techniques is required (see

Dosage and Administration

CHO/HGPRT mammalian cell forward gene mutation and unscheduled DNA synthesis

(UDS).

The bacteriostatic Water for Injections provided with Caverject contains benzyl alcohol,

which

is associated with severe adverse effects

including

fatal

“gasping syndrome”

paediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is

unknown. The risk of benzyl alcohol toxicity depends on the quantity administered and the

capacity of the liver and kidneys to detoxify the chemical. Premature and low birth weight

infants may be more likely to develop toxicity.

Effect on Fertility

reproductive

studies

indicate

that

subcutaneous

doses

alprostadil

2.0 mg/kg/day does not adversely affect or alter rat spermatogenesis.

Use in Pregnancy

Caverject

should

used

women

(see

Contraindications)

Alprostadil

abortifacient and stimulates uterine smooth muscle. Since PGE

occurs naturally in seminal

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fluid at doses greater than would be achieved if the Caverject were inadvertently injected into

the urethra the injected alprostadil would

not significantly

increase the activity of the

endogenous PGE

. However, patients should be advised that pregnant partners should

discuss the use of Caverject with their obstetrician.

Use in Lactation

Caverject should not be used in women (see

Contraindications

Paediatric Use

Caverject should not be used in paediatric patients (see

Contraindications

Genotoxicity

The following battery of mutagenicity assays revealed no potential for mutagenesis: bacterial

mutation (Ames), alkaline elution, rat micronucleus, sister chromatid exchange.

Carcinogenicity

Long-term carcinogenicity studies have not been conducted.

Effects on Ability to Drive and Use Machines

None known.

ADVERSE EFFECTS

The most frequent adverse reaction after intracavernosal injection of Caverject is mild to

moderate penile pain reported in approximately 11% of self-injections by men in clinical

studies. It was reported at least once by about one third of all patients, although only 3%

discontinued use for this reason. Penile fibrosis (including Peyronie's disease, angulation,

and fibrotic nodules), was reported in 3% of clinical trial patients overall, however, in one

self-injection study in which the duration of use was up to 18 months, the incidence of penile

fibrosis was approximately 8% (see

Warnings and Precautions

Hematoma

and ecchymosis at the site of

injection, which are related to the

injection

technique rather than to the effects of Caverject, occurred in 3% and 2% of patients,

respectively. Prolonged erection (defined as an erection that lasts for four to six hours) after

intracavernosal administration of Caverject was reported in 4% of patients. The frequency of

priapism (defined as an erection that lasts six hours or longer) was 0.4% (see

Warnings and

Precautions

). In the majority of cases, spontaneous detumescence occurred.

Haemodynamic changes, manifested as decreases in blood pressure at doses greater than

20 micrograms

increases

pulse

rate

doses

greater than

30 micrograms,

were

observed during clinical studies 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.

Adverse reactions reported by less than 1% of patients in clinical studies are listed in the table

below:

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Body system

Adverse Drug Reactions

Infections and

infestations

Yeast infection

Reproductive

system

and breast disorders

Scrotal oedema

Scrotal disorder (redness, pain, spermatocele)

Testicular disorder (warmth, swelling, mass, thickening)

Testicular pain

Haemosiderin deposits in the penis

Painful erection

Ejaculation abnormal

Penile deviations

Penile irritation

Penile warmth

Balanitis

Priapism

Pelvic pain

Perineal pain

Genital pain

Phimosis

Renal and urinary

disorders

Haematuria

Urinary frequency

Urinary urgency

Urination impaired

Urethral bleeding

Cardiac disorders

Supraventricular extrasystoles

Arrhythmia

Vascular disorders

Hypotension

Peripheral vascular disorder

Vasodilatation

Penile venous leak

Vagal shock

Nervous system

disorders

Vasovagal reaction

Hyperaesthesia (systemic)

Penile numbness

Decreased penile sensitivity

Collapse

Dizziness

Headache

Eye disorders

Mydriasis

Skin and

subcutaneous tissue

disorders

Rash

Pruritus

Diaphoresis

Erythema

Musculoskeletal,

connective tissue and

bone disorders

Leg cramps

Localised pain (buttocks, leg or back)

General disorders and

administration site

conditions

Injection site haemorrhage

Injection site inflammation

Injection site oedema

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Body system

Adverse Drug Reactions

Injection site pruritus

Injection site swelling

Localised muscle weakness

Gastrointestinal

disorders

Nausea

Dry mouth

Investigations

Blood creatinine increased

Changes in blood pressure

In some patients, these adverse events may be related to the injection procedure rather than to

the pharmacological effects of alprostadil.

INTERACTIONS

The potential for pharmacokinetic drug-drug interactions between Caverject and other agents

been

formally

studied.

clinical

trials,

concomitant

agents

such

antihypertensive drugs, diuretics, antidiabetic agents (including insulin), or non-steroidal anti-

inflammatory drugs had no effect on the safety or efficacy of Caverject. The safety and

efficacy

combinations

Caverject

other

vasoactive

agents

have

been

systematically studied.

OVERDOSAGE

Overdose data is limited. The pharmacologic signs of alprostadil are similar in all animal

species and include depression, soft stool or diarrhoea and rapid breathing.

In man, prolonged erection and/or priapism are known to occur following intracavernosal

administration of vasoactive substances, including alprostadil. Patients should be instructed

to report to a physician any erection lasting for a prolonged time period, such as 4 hours or

longer. Prolonged erection or priapism (lasting more than 6 hours) should be treated to

prevent tissue hypoxia and possible necrosis.

treatment

priapism

include

different

approaches

such

aspiration,

intracavernosal injection of sympathomimetic amines or surgery.

There is no antidote for alprostadil overdose. Treatment is symptomatic and supportive.

Support respiratory and cardiac function. Monitor pulmonary function, vital signs, ECG,

pulse oximetry, and fluid and electrolyte status in patients with significant diarrhoea.

Contact the National Poisons Centre on 0800 764 766 for advice on the management of an

overdose.

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PHARMACEUTICAL PRECAUTIONS

Instructions for Use/Handling

Parenteral drug products should be inspected visually for particulate matter and discoloration

prior to administration whenever the solution and container permit.

Bacteriostatic Water for Injections preserved with 9.45 mg/mL benzyl alcohol must be used

for reconstitution of Caverject. After reconstitution with 1 mL of diluent, the volume of the

resulting solution is 1.13 mL. Depending on vial strength, 1 mL of the reconstituted solution

will contain either 10.5 or 20.5 micrograms of alprostadil. The deliverable amount of

alprostadil is 10 or 20 micrograms/mL because approximately 0.5 micrograms is lost due to

adsorption to the vial and syringe.

Incompatibilities

Only

accompanying

bacteriostatic

Water

Injections

should

used

when

reconstituting Caverject.

Shelf life

Caverject should be stored at or below 25

The reconstituted solution should be used immediately. The reconstituted solution should not

be frozen.

MEDICINE CLASSIFICATION

Prescription Medicine.

PACKAGE QUANTITIES

Caverject containing 10 or 20 micrograms alprostadil is supplied in a pack of 1 5 mL glass

vial with a 1 mL prefilled diluent (bacteriostatic Water for Injections preserved with benzyl

alcohol) syringe, two needles (a 22 gauge needle for reconstitution and a 27 to 30 gauge

needle for injection) and two swabs.

FURTHER INFORMATION

Preclinical Data

A 1-year irritancy study was conducted in Cynomolgus monkeys injected intracavernosally

twice weekly with either vehicle or 3 or 8.25 micrograms of alprostadil per injection.

Additional monkeys were injected as described previously plus they received multiple doses

during weeks 44, 48, and 52. 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

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lesions noted were shown to be reversible. At the end of the 4-week recovery period, the

histological changes in the penis had regressed.

Chemical Structure

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

116°C. Its solubility at 35°C is 8000 micrograms/100 mL double distilled water. The acid

dissociation constant (Ka) is approximately 1.1 X 10

. The chemical name is (11a,13E,15S)-

11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. Molecular weight is 354.49. The structural

formula is as follows:

Excipients

Caverject Powder for Injection: Lactose monohydrate (diluent), α-cyclodextrine (stabiliser),

sodium citrate dihydrate (pH buffer), hydrochloric acid solution 10% (adjust pH), sodium

hydroxide solution (adjust pH), benzyl alcohol (preservative), Water for Injections (solvent).

NAME AND ADDRESS

Pfizer New Zealand Limited

P O Box 3998

Auckland 1140

New Zealand.

Toll Free Number: 0800 736 363.

DATE OF PREPARATION

11 April 2016.

Registered trademark.

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