LYRINEL 5mg, 10mg

2012 ילויב
Lyrinel_PI_22_July_12_CL 1
רשואו קדבנ ונכותו תואירבה דרשמ י"
ע עבקנ הז ןולע טמרופ
1. NAME OF THE MEDICINAL PRODUCT
Tradename
LYRINEL 5mg, 10mg ®
International Non-Proprietary Name
Oxybutynin chloride
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each extended [prolonged] release tablet contains 5 mg or 10 mg of oxybutynin chloride
3. PHARMACEUTICAL FORM
Extended [prolonged] release tablets for oral use:
• 5 mg: Pale yellow, round, tablet with “5 XL” printed on one side with black ink.
• 10 mg: Pink, round, tablet with “10 XL” printed on one side with black ink.
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Once daily controlled-release tablet indicated for the treatment of overactive bladder
with symptoms of urge urinary incontinence, urgency and frequency.
4.2. Posology and Method of Administration
LYRINEL is administered orally once daily.
The recommended starting dose of LYRINEL is 5 or 10 mg once daily. Dosage may be
adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum
of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.
[Patients already taking immediate release oxybutynin may be switched to the nearest
equivalent total daily dose of LYRINEL.]

LYRINEL must be swallowed whole with the aid of liquids, and must not be chewed, divided,
or crushed.
LYRINEL may be administered with or without food (see Section 5.2, Pharmacokinetic
Properties).
Elderly[≥65 years old]:
Same as for adults.
4.3. Contraindications
LYRINEL is contraindicated:
• - Hypersensitivity to oxybutynin or any of the excipients
• - Narrow-angle glaucoma or shallow anterior chamber
• - Myasthenia gravis
• - Urinary retention
• - Gastrointestinal obstructive disorder, paralytic ileus or intestinal atony
• - Severe ulcerative colitis
• - Toxic megacolon
• - Urinary frequency and nocturia due to heart or renal failure
• - Porphyria
4.4. Special Warnings and Special Precautions for Use
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (See
Section 4.8 Undesirable Effects). Patients should be monitored for signs of anticholinergic
CNS effects, particularly in the first few months after beginning treatment or increasing the
dose. If a patient experiences anticholinergic CNS effects, dose reduction or drug
discontinuation should be considered.
Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some
cases, angioedema occurred after the first dose. Angioedema associated with upper airway
swelling has the potential to become life-threatening. If involvement of the tongue,
hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate
therapy and/or measures necessary to ensure a patent airway should be promptly provided.
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Heat prostration (fever and heat stroke due to decreased sweating) can occur when
anticholinergics such as oxybutynin chloride are administered in the presence of high
environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence) or
blurred vision, patients should be advised to exercise caution.
LYRINEL should be given with caution in patients with the following conditions:
• hepatic or renal impairment;
• clinically significant bladder outflow obstruction because of the risk of urinary
retention (see Section 4.3, Contraindications);
• gastrointestinal obstructive and gastrointestinal motility disorders because of risk of
gastric retention (see Section 4.3, Contraindications);
• conditions such as ulcerative colitis due to the potential for decreased gastrointestinal
motility;
• myasthenia gravis due to the risk of symptom aggravation;
• gastroesophageal reflux and/or who are concurrently taking drugs (such as
bisphosphonates) that can cause or exacerbate esophagitis;
• preexisting severe gastrointestinal narrowing (pathologic or iatrogenic);
• preexisting dementia treated with cholinesterase inhibitors due to the risk of
aggravation of symptoms.
TRADENAME must be swallowed whole with the aid of liquids, and must not be chewed,
divided, or crushed. The medication is contained within a nonabsorbable shell designed to
release the drug at a controlled rate. The tablet shell is eliminated from the body; patients
should not be concerned if they occasionally notice something that looks like a tablet in their
stool.
Paediatric population
Oxybutynin hydrochloride is not recommended for use in children below age 5 years due to
insufficient data on safety and efficacy.
There is limited evidence supporting the use of Oxybutynin in children with monosymptomatic
nocturnal enuresis (not related to detrusor overactivity).
In children over 5 years of age, Oxybutynin hydrochloride should be used with caution as they
may be more sensitive to the effects of the product, particularly the CNS and psychiatric
adverse reactions.
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4.5. Interactions with Other Medicinal Products and Other Forms of
Interaction
The concomitant use of oxybutynin with other anticholinergic medicinal products or drugs
with anticholinergic activity, such as amantadine and other anticholinergic antiparkinsonian
drugs (e.g. biperiden, levodopa), antihistamines, antipsychotics (e.g. phenothiazines,
butyrophenones, clozapine), quinidine, tricyclic antidepressants, atropine and related
compounds like atropinic antispasmodics, dipyridamole, may increase the frequency or
severity of dry mouth, constipation and drowsiness.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. They may also
antagonize the gastrointestinal prokinetic effects of metoclopramide and domperidone.
However, the interaction between prokinetics and oxybutynin has not been established.
Sublingual nitrates may fail to dissolve under the tongue owing to dry mouth, resulting in
reduced therapeutic effect.
Oxybutynin is metabolised by cytochrome P450 isoenzyme CYP3A4. Mean oxybutynin
chloride concentrations were approximately 2 fold higher when Lyrinel XL was administered
with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of cytochrome P450 3A4
enzyme system, such as antimycotic agents (e.g. itraconazole and fluconazole) or macrolide
antibiotics (e.g. erythromycin), may alter oxybutynin pharmacokinetics. The clinical relevance
of such potential interaction is not known. Caution should be used when such drugs are coadministered.
4.6. Pregnancy and Lactation
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed
no evidence of impaired fertility or harm to the animal fetus. The safety of LYRINEL
administered to women who are or who may become pregnant has not been established.
Consequently, risks and potential benefits should be considered before this drug is administered
to pregnant patients.
It is not known whether oxybutynin is excreted in human milk. Caution should be exercised if
LYRINEL is administered to a nursing woman.
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4.7. Effects on Ability to Drive and Use Machines
No studies have been performed on the effect of LYRINEL on the ability to drive and use
machines. Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence) or blurred vision, patients should be advised to exercise caution.
4.8. Undesirable Effects
The table below reflects the data obtained with Lyrinel XL in clinical trials and from
postmarketing experience. In clinical trials with Lyrinel XL (n=1006), adverse events were
associated mainly with the anticholinergic actions of oxybutynin. Adverse events were generally
dose related. As with other oxybutynin formulations, dry mouth was the most frequently
reported adverse reaction. However, in clinical studies, dry mouth has been less frequently
reported with Lyrinel XL than with oxybutynin immediate release formulations. For patients
who required final doses of 5 or 10 mg of Lyrinel XL, the relative incidence of dry mouth that
occurred at any dose level was 1.8 times lower compared with patients who required final doses
> 10 mg.
Infections
and
infestations
Blood and
Lymphatic
system
disorders:
Immune
System
Disorders
Metabolism
& Nutrition
Disorders
Very
Commo
n
1/10
Common
1/100 to

Psychiatric
disorders
Nervous
System
Disorders
insomnia,
depression,
nervousness,
confusional state
somnolence,
headache,
dizziness,
dysgeusia
Eye disorders vision blurred,
dry eye,
keratoconjunctiv
itis sicca
Cardiac
disorders
Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointesti
nal Disorders
dry
mouth
Lyrinel_PI_22_July_12_CL 6
a
anxiety,
abnormal
dreams
paraesthesia,
vertigo
hypertonia,
tremor, tinnitus
conjunctivitis diplopia,
glaucoma,
photophobia
palpitations atrial
arrhythmia,
bradycardia,
bundle branch
block, nodal
arrhythmia,
supraventricula
r extrasystoles
hypertension vasodilatation,
migraine
nasal dryness,
mucosal
dryness, cough,
pharyngolaryngeal
pain,
dry throat
constipation,
diarrhoea,
nausea,
dyspepsia,
abdominal pain,
flatulence,
rhinitis,
hoarseness,
epistaxis,
dyspnoea
dysphagia,
mouth
ulceration,
abdominal
distension,
glossitis,
hypotension,
phlebitis,
ecchymosis
laryngitis,
laryngeal
oedema,
respiratory
disorder,
sputum
increased
faecal
abnormality,
oesophageal
stenosis
acquired,
gastritis,
hallucinations,
night terror,
psychotic
disorder,
agitation,mem
ory
impairment
convulsions
arrhythmia
tachycardia
flushing

Skin and
subcutaneous
tissue
disorders
Musculoskele
tal and
connective
tissue
disorders
Renal and
urinary
disorders
Reproductive
system and
breast
disorders
General
disorders and
administratio
n site
conditions
gastroesophagea
l reflux disease,
loose stools,
vomiting
dry skin, pruritus acne, urticaria,
face oedema,
alopecia,
eczema, nail
disorder, skin
discolouration,
anhidrosis
pain in
extremity, back
pain, arthralgia
micturition
disorder,
residual urine
volume, urinary
retention,
dysuria, urinary
hesitation
asthenia,
oedema
peripheral,
fatigue, chest
pain
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stomatitis gastroenteritis
viral, hernia,
rectal disorder,
gastric atony,
tongue
disorder,
tongue oedema
muscle cramps,
myalgia
urinary
frequency,
urinary tract
disorder,
haematuria,
nocturia,
pyuria,
micturition
urgency
breast pain,
vaginitis
pain, thirst,
oedema
hair disorder,
rash maculopapular,
granuloma,
sweating
increased,
photosensitivit
y reaction
arthritis
urinary
incontinence,
urine
abnormal,
urogenital
disorder
vulvovaginal
disorder,
uterine cervical
disorder,
genital
discharge
rigor, pyrexia,
influenza like
illness,
malaise, pelvic
pain
rash
impotence,
erectile
dysfunction

Investigations blood pressure
increased
Injury,
poisoning
and
procedural
complications
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electrocardiogr
am abnormal,
blood urea
increased,
blood
creatinine
increased
*Cannot be estimated from the available clinical data.
blood alkaline
phosphatase
increased,
blood lactase
dehydrogenase
increased,
blood
aspartate,
aminotransfera
se increased,
blood alanine
aminotransfera
se increased
Undesirable effects noted with other oxybutynin hydrochloride formulations:
In addition, cyclopegia, mydriasis and suppression of lactation have been reported with the use
of other oxybutynin hydrochloride formulations.
4.9. Overdose
The symptoms of overdose with oxybutynin progress from an intensification of the usual CNS
disturbances (from restlessness and excitement to psychotic behaviour), circulatory changes
(flushing, fall in blood pressure, circulatory failure etc.), respiratory failure, paralysis and
coma.
Measures to be taken are:
1) administration of activated charcoal
2) physostigmine by slow intravenous injection:
Fever should be treated symptomatically with tepid sponging or ice packs.
fall

In pronounced restlessness or excitation, diazepam may be given by intravenous injection.
Tachycardia may be treated with intravenous propranolol and urinary retention managed by
bladder catheterisation.
In the event of progression of curare-like effects to paralysis of the respiratory muscles,
mechanical ventilation will be required.
The continuous release of oxybutynin from Lyrinel XL should be considered in the treatment
of overdose. Patients should be monitored for at least 24 hours.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
[Pharmacotherapeutic group: ATC code: G04B D04 Urologicals]
Oxybutynin chloride is a synthetic tertiary amine with direct spasmolytic and anticholinergic
action on the smooth musculature of the detrusor muscle of the bladder. It increases bladder
capacity, reduces the frequency of uninhibited detrusor contractions, and delays the first urge to
urinate. Oxybutynin thus decreases the symptoms of urinary incontinence due to either
idiopathic detrusor instability or detrusor hyperreflexia.
5.2. Pharmacokinetic Properties
Absorption
Following the first dose of LYRINEL , oxybutynin plasma concentrations rise for 4 to 6 hours;
thereafter steady concentrations are maintained for up to 24 hours, minimizing fluctuations
between peak and trough concentrations associated with oxybutynin immediate release
formulations.
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The relative bioavailabilities of R- and S-oxybutynin from LYRINEL are 156% and 187%,
respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and Soxybutynin
are summarized in Table [4 or 5]. The plasma concentration-time profiles for Rand
S-oxybutynin are similar in shape.
Table [4 or 5] Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of
LYRINEL 10 mg (n=43)
Parameters
R-Oxybutynin S-Oxybutynin
(units)
Cmax
(ng/mL)
1.0 (0.6) 1.8 (1.0)
Tmax (h) 12.7 (5.4) 11.8 (5.3)
t ½ (h) 13.2 (6.2) 12.4 (6.1)
AUC(0-48)
(ng•h/mL)
AUCinf
(ng•h/mL)
18.4 (10.3) 34.2 (16.9)
21.3 (12.2) 39.5 (21.2)
Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated
TRADENAME dosing, with no observed drug accumulation or change in oxybutynin and
desethyloxybutynin pharmacokinetic parameters.
LYRINEL steady-state pharmacokinetics was studied in 19 children aged 5-15 years with
detrusor overactivity associated with a neurological condition (e.g., spina bifida). The
children were on LYRINEL total daily dose ranging from 5 to 20 mg (0.10 to 0.77 mg/kg).
Sparse sampling technique was used to obtain serum samples. When all available data are
normalized to an equivalent of 5 mg per day LYRINEL, the mean pharmacokinetic
parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized
in Table [5 or 6]. The plasma-time concentration profiles for R- and S-oxybutynin are similar
in shape; Figure 1 shows the profile for R-oxybutynin when all available data are normalized
to an equivalent of 5 mg per day.
Table [5 or 6] Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters in Children Aged 5-15 Following Administration of 5 to 20mg LYRINEL Once Daily
(N=19) All Available Data Normalized To An Equivalent of LYRINEL 5 mg Once Daily
R-Oxybutynin S-Oxybutynin R-Desethyl-oxybutynin S-Desethyl-oxybutynin
Cmax
(ng/mL)
0.7 ± 0.4 1.3 ± 0.8 7.8 ± 3.7 4.2 ± 2.3
Tmax (hr) 5.0 5.0 5.0 5.0
AUC
12.8 ± 7.0
(ng.hr/mL)
23.7 ± 14.4 125.1 ± 66.7 73.6 ± 47.7
Figure 1 Mean steady state (±SD) R-oxybutynin plasma concentrations following administration of 5 to 20 mg
LYRINEL once daily in children aged 5-15. All available data normalized to an equivalent of
LYRINEL 5 mg once daily
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Based on two separate pharmacokinetic studies that evaluated the concomitant use of
LYRINEL with an antacid and with a proton pump inhibitor, drugs that increase gastric pH do
not affect the release of drug from the tablet or resulting plasma concentrations of oxybutynin
and its metabolite, desethyloxybutynin.
Dose Proportionality
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following
administration of 5-20 mg of LYRINEL are dose proportional.
Distribution
Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of
distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride . Both
enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of
desethyloxybutynin are also highly bound (>97%) to plasma proteins. The major binding
protein is alpha-1 acid glycoprotein.
Metabolism and Excretion
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly
CYP3A4 found mostly in the liver and gut wall. Its metabolic products include
phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin,
which is pharmacologically active. Following LYRINEL administration, plasma concentrations
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of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed
with oxybutynin.
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered
dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted
as the metabolite desethyloxybutynin.
Food Effects
The rate and extent of absorption and metabolism of oxybutynin are similar under fed and
fasted conditions.
Special Populations
Gender: There are no significant differences in the pharmacokinetics of oxybutynin in healthy
male and female volunteers following administration of LYRINEL.
Geriatric: The pharmacokinetics of LYRINEL were similar in all patients studied (up to 78
years of age).
Race: Available data suggest that there are no significant differences in the pharmacokinetics
of oxybutynin based on race in healthy volunteers following administration of LYRINEL.
Renal Insufficiency: There is no experience with the use of LYRINEL in patients with renal
insufficiency.
Hepatic Insufficiency: There is no experience with the use of LYRINEL in patients with
hepatic insufficiency.
5.3. Preclinical Safety Data
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg/day
showed no evidence of carcinogenicity. These doses are approximately 6, 25 and 50 times the
maximum human exposure, based on surface area.
Oxybutynin chloride showed no mutagenic activity when tested in Schizosaccharomyces
pompholiciformis, Saccharomyces cerevisiae, and Salmonella typhimurium test systems.
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed
no evidence of impaired fertility.
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6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
LYRINEL also contains the following inert ingredients: cellulose acetate, hypromellose, ,
magnesium stearate, polyethylene glycol, polyethylene oxide 200K, polyethylene oxide 2000K,
Black iron oxide : lactose 95:5
5 mg: iron oxide green:lactose 95:5, opadry YS-1-12871-A light yellow
10 mg: red ferric oxide, opadry pink YS-1-14518-A
6.2. Incompatibilities
None known.
6.3. Special Precautions for Storage
Do not store above 25°C . Keep container tightly closed. Keep out of the reach of children.
6.4 Nature and contents of containers
High density polyethylene bottles with child resistant closure (polypropylene) and
desiccant.
Pack sizes 30 tablets
7. MARKETING AUTHORISATION HOLDER
J-C Health Care Ltd. Kibbutz Shefayim 60990
8. Manufacturer
Janssen Cilag SpA, Latina, Italy
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