|
back to top
1. Name of the Medicinal Product
Uprima 2 mg sublingual tablets
and Uprima 3 mg sublingual tablets
2. Qualitative and Quantitative
Composition
Each 2 mg tablet contains 2 mg
apomorphine hydrochloride, equivalent to 1.71 mg
apomorphine.
Each 3 mg tablet contains 3 mg
apomorphine hydrochloride, equivalent to 2.56 mg
apomorphine.
For excipients see 6.1.
3. Pharmaceutical Form
Sublingual tablets.
2 mg tablet is a brick red,
pentagon-shaped tablet embossed with "2" on
one side and the Abbott logo on the other side.
3 mg tablet is a brick red,
triangle-shaped tablet embossed with "3" on
one side and the Abbott logo on the other side.
4. Clinical Particulars
4.1 Therapeutic indications
Treatment of erectile
dysfunction, which is the inability to achieve or maintain
a penile erection sufficient for satisfactory sexual
performance.
In order for Uprima
to be effective, sexual stimulation is required.
Uprima is not indicated
for use by women.
4.2 Posology and method of administration
For sublingual use.
The tablet should be placed under the tongue and allowed
to dissolve.
Use in adults
One tablet should
be administered approximately 20 minutes prior to sexual
activity. It is recommended that the patient be started
at the 2 mg dose. The dose may be increased on
subsequent administrations to 3 mg if necessary
to reach the desired clinical effect.
A minimum time period
of 8 hours should be allowed to elapse prior to
administering a subsequent dose.
Each patient should
be instructed by a medical professional on the proper
administration technique for Uprima. The patient should
be advised to drink a small amount of water before taking
Uprima to optimise the dissolution of the tablet. One
tablet of Uprima should be placed under the tongue.
In the majority of patients the tablet will be completely
dissolved within 10 minutes. If any residual amount
remains in the mouth after 20 minutes it may be
swallowed. In order for Uprima to be effective, sexual
stimulation is required. The patient should initiate
sexual activity and proceed to intercourse when he feels
ready. The median onset of effect is approximately 18 - 19
minutes after the tablet is placed under the tongue;
the onset time varies from patient to patient.
Use in the elderly
No dosage adjustment
is required in elderly patients.
Use in patients
with impaired renal function
In patients with
renal insufficiency an increase in apomorphine AUC values
and prolongation of the elimination half-life was observed,
however, Cmax was not significantly altered.
The maximum dosage should therefore be limited to 2 mg
in patients with severely impaired renal function.
Use in patients
with impaired hepatic function
In patients with
hepatic insufficiency significant increases were observed
in apomorphine AUC values, Cmax and elimination
half-life. Owing to the potential for a higher risk
of adverse events in this population, patients with
significantly impaired hepatic function should only
be given Uprima if the benefits outweigh the risks.
Such patients may be initiated at the 2 mg dosage
level and care exercised in any dose increase.
Use in children
Uprima is not indicated
for use in children.
4.3 Contraindications
Uprima is contraindicated
in the following situations:
In patients with known hypersensitivity
to the active substance or any of the excipients in
the tablet formulation.
In patients with severe unstable
angina, recent myocardial infarction, severe heart failure
or hypotension and other conditions where sexual activity
is inadvisable.
4.4 Special warnings and special
precautions for use
A medical history
and a complete physical examination should be conducted
in order to diagnose erectile dysfunction and determine
the underlying causes before pharmacological treatment
is considered. Before commencement of any treatment
for erectile dysfunction, the potential cardiac risks
inherent in resuming sexual activity in an individual
patient, assessed according to his medical condition
and history, should be considered by the physician.
It is not known
if Uprima is effective in patients with spinal cord
injuries, multiple sclerosis, and in patients who have
undergone prostatectomy or pelvic surgery. Efficacy
in diabetic patients has not been established.
Agents for the treatment
of erectile dysfunction should be used with caution
in patients with anatomical penile deformity (such as
angulation, cavernosal fibrosis, or Peyronie’s
disease) , as Uprima has not been sufficiently studied
in these populations.
Uprima may uncommonly
produce a transient vasovagal syndrome that may manifest
as a self-limiting fainting/syncope (incidence <0.2 %
at the recommended dose regimen). Nearly all (> 90 %)
syncopal episodes were preceded by a prodrome of symptoms
that included mild to severe nausea, vomiting, pallor,
sweating/hot flushes, and dizziness or lightheadedness.
If patients experience prodromal symptoms they should
not attempt to stand up, but should lie down and raise
their legs until their symptoms resolve.
Uprima should be
used with caution in patients with uncontrolled hypertension,
known hypotension or those with a history of postural
hypotension. Acute decreases in blood pressure have
been noted after Uprima administration. Elderly patients
may be more prone to such occurrences and are more susceptible
to any deleterious consequences.
Uprima should be
used with caution in patients taking antihypertensives
or nitrate medications owing to the potential for hypotension
(see section 4.5 Interaction with other medicinal products
and other forms of interaction).
Uprima should be
used with caution in patients with compromised renal
or hepatic function (see section 4.2 Posology and method
of administration).
The safety and efficacy of Uprima
in combination with other treatments for erectile dysfunction
has not been studied. Therefore, the use of such combinations
is not recommended.
4.5 Interaction with other medicinal
products and other forms of interaction
Since apomorphine is primarily metabolised
by sulphation and glucuronidation, compounds that inhibit
or induce cytochrome P450 isoforms are not expected
to affect the pharmacokinetics of apomorphine.
The combination of Uprima with both
nitrates and antihypertensives (angiotensin-converting
enzyme (ACE) inhibitors, b -blockers, calcium channel
blockers, and alpha1 blockers) has been studied.
The only significant findings were in the group of patients
who were taking nitrates. A proportion (4/40) of these
patients experienced vasovagal symptoms and significant
standing blood pressure decreases when Uprima was administered
at higher than the recommended dose (5 mg). It
is therefore recommended that caution be observed when
administering Uprima to patients taking nitrates.
Interaction studies and/or clinical
experience with ondansetron hydrochloride, prochlorperazine
maleate, and domperidone indicate that these agents
may be given safely with Uprima. No studies have been
performed with Uprima in combination with other antiemetics,
hence other combinations are not recommended.
Uprima should not be given in combination
with other centrally-acting dopamine agonists or antagonists
because of the potential for pharmacodynamic interactions.
No formal drug interaction studies
have been performed with other agents for erectile dysfunction,
antidepressants, anticonvulsants or other CNS-active
agents, however clinical experience has not indicated
the presence of interactions.
Interaction studies in volunteers
where alcohol was given with Uprima indicated that concurrent
alcohol intake may cause an increase in the incidence
and extent of hypotension.
Additionally, intake of alcohol
can diminish sexual performance.
4.6 Pregnancy and lactation
Uprima is not indicated for use
in women.
Animal reproduction
studies have not been conducted with Uprima. It is not
known whether Uprima can cause foetal harm in pregnant
women or whether it can affect female reproduction capacity.
Also, it is not known whether apomorphine passes into
breast milk.
4.7 Effects on ability to drive
and use machines
No studies on the
effects on the ability to drive and use machines have
been performed. Because some patients can experience
dizziness, lightheadedness, and, uncommonly, syncope,
they should not engage in activities such as driving
or operating machinery for at least 2 hours after administration
of Uprima or until any such symptoms are fully resolved.
4.8 Undesirable effects
Over 4000 patients
have received at least one dose of Uprima in clinical
trials. The most common (>1/100, <1/10) adverse
drug reactions noted in patients taking 2 – 3 mg
Uprima are nausea and headache, both occurring in approximately
7 % of patients, and dizziness, occurring in approximately
4 % of patients.
Other commonly (>1/100,
<1/10) observed adverse drug reactions are yawning,
rhinitis, pharyngitis, somnolence, infection, pain,
increased cough, flushing, taste disorder, and sweating.
These adverse events were generally mild and transient.
Uncommonly (>1/1000,
<1/100), Uprima may produce a transient vasovagal
syndrome that can lead to self-limiting fainting/syncope.
(See section 4.4 Special warnings and precautions for
use).
4.9 Overdose
Uprima in high doses
may induce vomiting. If the tablets are swallowed the
bioavailability of apomorphine will be reduced by first
pass metabolism. There is no specific antidote available
for Uprima. Treatment should be supportive and symptomatic.
It is advised that vital signs such as blood pressure
and heart rate are monitored. Measures to avoid possible
orthostatic hypotension should be taken. The use of
domperidone maleate, a peripherally acting dopamine
antagonist used to counter emetic effects, may be considered.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs
used in erectile dysfunction (ATC code: G04B E).
Apomorphine is a sublingual therapy
for the treatment of erectile dysfunction and operates
through a central mechanism of action. It is predominantly
a D2-like dopaminergic agonist with selectivity for
D2, D3 and D4 receptors that is from 10-100 fold greater
than for D1 and D5 in relevant cells. It acts within
the central nervous system, particularly the hypothalamic
region of the brain, which is known to be involved in
the mediation of erection. The erectogenic effects of
apomorphine arise through dopaminergic signalling via
oxytocinergic pathways. These signals subsequently mediate
local actions of nitric oxide, the conversion of GTP
to cGMP, and subsequent smooth muscle relaxation in
the corpus cavernosum, leading to corporal engorgement
and erection.
The clinical pharmacodynamic profile
of apomorphine is consistent with its dopaminergic activity.
In Phase III studies, Uprima at
2 mg and 3 mg was statistically superior to
placebo for the primary endpoint of percentage of intercourse
attempts resulting in erections firm enough for intercourse,
showing a response of about 45 % with 2 mg
(as compared to about 35 % with placebo) and about
50 % with 3 mg (as compared to about 30 %
with placebo).
The median onset time to erection
for Uprima was approximately 18 - 19 minutes
(confidence intervals approximately 16 - 21
minutes).
5.2 Pharmacokinetic properties
Following sublingual administration,
apomorphine reaches peak plasma concentrations relatively
quickly (see below). Apomorphine is rapidly cleared
from plasma, with an apparent elimination half-life
of approximately 3 hours. Due to extensive first pass
metabolism, Uprima appears to be nearly ineffective
when swallowed, with only 1 – 2 %
of the activity seen after intravenous or subcutaneous
administration.
Absorption: apomorphine is rapidly
absorbed from the sublingual cavity and can be detected
in plasma within 10 minutes after placing the tablet
under the tongue. Peak plasma concentrations are attained
in about 40 – 60 minutes. Increasing dosage strengths
of Uprima sublingual tablets provide dose-proportional
increases in Cmax and AUC„ . The bioavailability
of apomorphine from sublingual tablets, relative to
subcutaneous administration, is approximately 17 –18 %.
Distribution: apomorphine is
approximately 90 % bound to plasma proteins, primarily
albumin. Binding is independent of concentration between
1.0 and 1000 ng/ml, which exceeds the concentration
range achieved with the recommended doses.
Metabolism: apomorphine is extensively
metabolised, primarily through conjugation with glucuronic
acid or sulphate. Apomorphine is also metabolised by
N-demethylation, leading to the formation of
norapomorphine, which is converted to glucuronide and
sulphate conjugates. The major metabolite in plasma
of subjects receiving a single sublingual dose of apomorphine
is apomorphine sulphate. The glucuronides of apomorphine
and norapomorphine are found in plasma at lower concentrations.
These conjugates are not expected to be pharmacologically
active. In vitro data suggest that Uprima at
the recommended doses, is not likely to inhibit the
metabolism of other drugs by cytochrome P450 isoforms
CYP1A2, 3A4, 2C9, 2C19 or 2D6.
Elimination: following a 2 mg
sublingual dose of [14C] apomorphine, radioactivity
was eliminated in both urine (93 %) and faeces
(16 %). Less than 2 % of the apomorphine dose
was excreted in urine as free apomorphine.
Special Populations:
Elderly
The pharmacokinetics of apomorphine
(5 mg) were investigated in healthy male subjects
older than 65 years. The tmax was 36 %
longer and the Cmax was 21 % lower in
elderly subjects than in young subjects. The AUC was
11 % larger in the elderly. See section 4.2 Posology
and method of administration for dosage recommendations.
Renal insufficiency
The AUC of apomorphine was increased
by 4 % in subjects with mild renal insufficiency
(creatinine clearance 40 – 80 ml/min/1.73 m2
), 52 % in moderate cases (10 – 40 ml/min/1.73 m2)
and 67 % in severe cases (< 10 ml/min/1.73 m2).
Apparent terminal elimination half-life of apomorphine
was predicted to increase by 0.24 hour with each
10ml/min/1.73 m2 decrease in creatinine
clearance. Cmax was not significantly affected.
See section 4.2 Posology and method of administration
for dosage recommendations.
Hepatic insufficiency
Mean Cmax and AUC were
16 – 62 % and 35 – 68 %
higher, respectively, in subjects with varying degrees
of hepatic insufficiency compared with normal subjects.
The apparent terminal elimination half-life of apomorphine
2 mg was 1.8 – 3.5 hours in patients
with hepatic insufficiency compared with 1.9 hours
in normal subjects. See section 4.2 Posology and method
of administration for dosage recommendations.
5.3 Preclinical safety data
Preclinical data revealed no special
hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and
carcinogenicity. Apomorphine has no effect on fertility
in male rats. Findings observed in animals included
behavioural disorders, retinal atrophy, Leydig cell
tumours, and haematological changes. All of these events
occurred at exposure levels much higher than those used
in clinical trials, were species-specific, and they
are not considered relevant to the clinical use of Uprima.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose
Hypromellose
Citric acid
Magnesium stearate
Ascorbic acid
Disodium edetate
Silicon dioxide
Red iron oxide (E172)
Acesulfame potassium
Orange mint flavour (WONF WL-28499)
Mannitol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package.
6.5 Nature and contents of container
Uprima 2 mg sublingual tablets:
Aluminium foil/foil cold-form blister
packs containing 2 or 4 sublingual tablets.
Uprima 3 mg sublingual tablets:
Aluminium foil/foil cold-form blister
packs containing 2 or 4 sublingual tablets
6.6 Instructions for use and handling
Not applicable.
7. MARKETING AUTHORISATION HOLDER
Abbott Laboratories Ltd
Queenborough
Kent ME11 5EL
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
Uprima 2 mg 2 Tablet pack EU/1/01/180/002
Uprima 2 mg 4 Tablet pack EU/1/01/180/004
Uprima 3 mg 2 Tablet pack EU/1/01/180/007
Uprima 3 mg 2 Tablet pack EU/1/01/180/008
9. DATE OF FIRST AUTHORISATION/RENEWAL
OF THE AUTHORISATION
28th May 2001
10. DATE OF REVISION OF THE TEXT
28th May 2001
back
to top
|
