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RALVO 700 MG MEDICATED PLASTER

Active substance(s): LIDOCAINE / LIDOCAINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT

Ralvo 700 mg medicated plaster

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 10 cm x 14 cm plaster contains 700 mg lidocaine (5%w/w)
Excipients with known effect:
Methyl parahydroxybenzoate (E218) 14 mg
Propyl parahydroxybenzoate (E216) 7 mg
Propylene glycol (E1520) 700 mg
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Medicated plaster
White hydrogel plaster containing adhesive material, which is applied to a non-woven
polyethylene terephthalate backing embossed with “Lidocaine 5%” and covered with
a polyethylene terephthalate film release liner.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Ralvo is indicated for the symptomatic relief of neuropathic pain associated with
previous herpes zoster infection (post-herpetic neuralgia, PHN) in adults.

4.2

Posology and method of administration

Adults and elderly patients

The painful area should be covered with the plaster once daily for up to 12 hours
within a 24 hours period. Only the number of plasters that are needed for an effective
treatment should be used. When needed, the plasters may be cut into smaller sizes
with scissors prior to removal of the release liner. In total, not more than three plasters
should be used at the same time.
The plaster must be applied to intact, dry, non-irritated skin (after healing of the
shingles).
Each plaster must be worn no longer than 12 hours. The subsequent plaster-free
interval must be at least 12 hours. The plaster can be applied during the day or during
the night.
The plaster must be applied to the skin immediately after removal from the sachet and
following removal of the release liner from the gel surface. Hairs in the affected area
must be cut off with a pair of scissors (not shaved).
Treatment outcome should be re-evaluated after 2-4 weeks. If there has been no
response to Ralvo after this period (during the wearing time and/or during the plasterfree interval), treatment must be discontinued as potential risks may outweigh benefits
in this context (see sections 4.4 and 5.1). Long-term use of Ralvo in clinical studies
showed that the number of plasters used decreased over time. Therefore treatment
should be reassessed at regular intervals to decide whether the amount of plasters
needed to cover the painful area can be reduced, or if the plaster-free period can be
extended.
Renal impairment
In patients with mild or moderate renal impairment a dosage adjustment is not
required.
Ralvo should be used with caution in patients with severe renal impairment (see
section 4.4).
Hepatic impairment
In patients with mild or moderate hepatic impairment a dosage adjustment is not
required.
Ralvo should be used with caution in patients with severe hepatic impairment (see
section 4.4).
Paediatric population
The safety and efficacy of Ralvo in children below 18 years has not been established.
No data are available.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section
6.1. The plaster is also contraindicated in patients with known hypersensitivity to
other local anaesthetics of the amide type e.g. bupivacaine, etidocaine, mepivacaine
and prilocaine.
The plaster must not be applied to inflamed or injured skin, such as active herpes
zoster lesions, atopic dermatitis or wounds.

4.4

Special warnings and precautions for use

The plaster should not be applied to mucous membranes. Eye contact with the plaster
should be avoided.
The plaster contains propylene glycol (E1520) which may cause skin irritation. It also
contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate
(E216) which may cause allergic reactions (possibly delayed).
The plaster should be used with caution in patients with severe cardiac impairment,
severe renal impairment or severe hepatic impairment.
One of the lidocaine metabolites, 2,6 xylidine, has been shown to be genotoxic and
carcinogenic in rats (see section 5.3). Secondary metabolites have been shown to be
mutagenic. The clinical significance of this finding is unknown. Consequently long
term treatment with Ralvo is only justified if there is a therapeutic benefit for the
patient (see section 4.2).

4.5

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. No clinically relevant interactions have
been observed in clinical studies with the plaster.
Since the maximum lidocaine plasma concentrations observed in clinical trials with
the plaster were low (see section 5.2), a clinically relevant pharmacokinetic
interaction is unlikely.
Although normally the absorption of lidocaine from the skin is low, the plaster must
be used with caution in patients receiving Class I antiarrhythmic medicinal products
(e.g. tocainide, mexiletine) and other local anaesthetics since the risk of additive
systemic effects cannot be excluded.

4.6

Fertility, pregnancy and lactation

Pregnancy
Lidocaine crosses the placenta. However, there are no adequate data from the use of lidocaine
in pregnant women.
Animal studies do not indicate a teratogenic potential for lidocaine (see section 5.3).
The potential risk for humans is unknown. Therefore, Ralvo should not be used during
pregnancy unless clearly necessary.

Breast-feeding
Lidocaine is excreted in breast milk. However, there are no studies of the plaster in
breast-feeding women. Since the metabolism of lidocaine occurs relatively fast and
almost completely in the liver, only very low levels of lidocaine are expected to be
excreted into human milk.
Fertility

No clinical data regarding fertility are available. Animal studies have not shown
effects on female fertility.

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. An effect on the ability to drive and use machines is unlikely because
systemic absorption is minimal (see section 5.2)

4.8

Undesirable effects

Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Approximately 16% of patients can be expected to experience adverse reactions.
These are localised reactions due to the nature of the medicinal product.
The most commonly reported adverse reactions were administration site reactions
(such as burning, dermatitis, erythema, pruritus, rash, skin irritation, and vesicles).
The table below lists adverse reactions that have been reported in studies of post
herpetic neuralgia patients receiving the plaster. They are listed by system organ class
and frequency. Frequencies are defined as very common (≥1/10); common (≥1/100 to
<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare
(<1/10,000), not known (cannot be estimated from the available data).
Body system
Adverse drug reaction
Skin and subcutaneous tissues
disorders
Uncommon
Skin lesion
Injury, poisoning and procedural
complications
Uncommon
Skin injury
General disorders and
administration site conditions
Very common
Administration site reactions
The following reactions have been observed in patients receiving the plaster under
post-marketing conditions:
Body system
Adverse drug reaction
Injury, poisoning and procedural
complications
Very rare
Open wound
Immune system disorders
Very rare
Anaphylactic reaction,
hypersensitivity

All adverse reactions were predominantly of mild and moderate intensity. Of those
less than 5% lead to treatment discontinuation.
Systemic adverse reactions following the appropriate use of the plaster are unlikely
since the systemic concentration of lidocaine is very low (see section 5.2). Systemic
adverse reactions to lidocaine are similar in nature to those observed with other amide
local anaesthetic agents (see section 4.9).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose

Overdose with the plaster is unlikely but it cannot be excluded that inappropriate use, such as
use of a higher number of plasters at the same time, with prolonged application period, or
using the plaster on broken skin might result in higher than normal plasma concentrations.
Possible signs of systemic toxicity will be similar in nature to those observed after
administration of lidocaine as a local anaesthetic agent, and may include the following signs
and symptoms:
dizziness, vomiting, drowsiness, seizures, mydriasis, bradycardia, arrhythmia, and shock.
In addition, known drug interactions related to systemic lidocaine concentrations with betablockers, CYP3A4 inhibitors (e.g. imidazole derivatives, macrolides) and antiarrhythmic
agents might become relevant with overdose.
In case of suspected overdose the plaster should be removed and supportive measures taken as
clinically needed. There is no antidote to lidocaine.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: local anaesthetics, amides
ATC code: N01 BB02
Mechanism of action
Ralvo has a dual mode of action: the pharmacological action of lidocaine diffusion and the
mechanical action of the hydrogel plaster that protects the hypersensitive area.
The lidocaine contained in the Ralvo plaster diffuses continuously into the skin, providing a
local analgesic effect. The mechanism by which this occurs is due to stabilisation of neuronal
membranes, which is thought to cause down regulation of sodium channels resulting in pain
reduction.
Clinical efficacy

Pain management in PHN is difficult. There is evidence of efficacy with Ralvo in the
symptomatic relief from the allodynic component of PHN in some cases (see section 4.2).
Efficacy of Ralvo has been shown in post-herpetic neuralgia studies.
There were two main controlled studies carried out to assess the efficacy of the lidocaine 700
mg medicated plaster.
In the first study, patients were recruited from a population who were already considered to
respond to the product. It was a cross over design of 14 days treatment with lidocaine 700 mg
medicated plaster followed by placebo, or vice versa. The primary endpoint was the time to
exit, where patients withdrew because their pain relief was two points lower than their normal
response on a six point scale (ranging from worse to complete relief). There were 32 patients,
of whom 30 completed. The median time to exit for placebo was 4 days and for active was 14
days (p value < 0.001); none of those on active discontinued during the two week treatment
period.
In the second study 265 patients with post-herpetic neuralgia were recruited and allocated
eight weeks of open label active treatment with lidocaine 700 mg medicated plaster. In this
uncontrolled setting approximately 50% of patients responded to treatment as measured by at
least four points on a six point scale (ranging from worse to complete relief). A total of 71
patients were randomised to receive either placebo or lidocaine 700 mg medicated plaster
given for 2-14 days. The primary endpoint was defined as lack of efficacy on two consecutive
days because their pain relief was two points lower than their normal response on a six point
scale (ranging from worse to complete relief) leading to withdrawal of treatment. There were
9/36 patients on active and 16/35 patients on placebo who withdrew because of lack of
treatment benefit.
Post hoc analyses of the second study showed that the initial response was independent of the
duration of pre-existing PHN. However, the notion that patients with longer duration of PHN
(> 12 months) do benefit more from active treatment is supported by the finding that this
group of patients was more likely to drop out due to lack of efficacy when switched to
placebo during the double-blind withdrawal part of this study.
In a controlled open-label study Ralvo suggested comparable efficacy to pregabalin in 98
patients with PHN with a favourable safety profile.

5.2

Pharmacokinetic properties

Absorption
When lidocaine 700 mg medicated plaster is used according to the maximum
recommended dose (3 plasters applied simultaneously for 12 h) about 3 ± 2% of the
total applied lidocaine dose is systemically available and similar for single and
multiple administrations.
A population kinetics analysis of the clinical efficacy studies in patients suffering
from PHN revealed a mean maximum concentration for lidocaine of 45 ng/ml after
application of 3 plasters simultaneously 12 h per day after repeated application for up
to one year. This concentration is in accordance with the observation in
pharmacokinetic studies in PHN patients (52 ng/ml) and in healthy volunteers (85
ng/ml and 125 ng/ml).
For lidocaine and its metabolites MEGX, GX, and 2,6-xylidine no tendency for
accumulation was found, steady state concentrations were reached within the first four
days.

The population kinetic analysis indicated that when increasing the number from 1 to 3
plasters worn simultaneously, the systemic exposure increased less than
proportionally to the number of used plasters.
Distribution
After intravenous administration of lidocaine to healthy volunteers, the volume of
distribution was found to be 1.3 ± 0.4 l/kg (mean ± S.D., n = 15). The lidocaine
distribution volume showed no age-dependency, it is decreased in patients with
congestive heart failure and increased in patients with liver disease. At plasma
concentrations produced by application of the plaster approximately 70 % of lidocaine
is bound to plasma proteins. Lidocaine crosses the placental and blood brain barriers
presumably by passive diffusion.
Biotransformation
Lidocaine is metabolised rapidly in the liver to a number of metabolites. The primary
metabolic route for lidocaine is N-dealkylation to monoethylglycinexylidide (MEGX)
and glycinexylidide (GX), both of which are less active than lidocaine and available
in low concentrations. These are hydrolyzed to 2,6-xylidine, which is converted to
conjugated 4-hydroxy-2,6-xylidine.
The metabolite, 2,6-xylidine, has unknown pharmacological activity but shows
carcinogenic potential in rats (see section 5.3). A population kinetics analysis revealed
a mean maximum concentration for 2,6-xylidine of 9 ng/ml after repeated daily
applications for up to one year. This finding is confirmed by a phase I
pharmacokinetic study. Data on lidocaine metabolism in the skin are not available.
Elimination
Lidocaine and its metabolites are excreted by the kidneys. More than 85 % of the dose
is found in the urine in the form of metabolites or active substance. Less than 10 % of
the lidocaine dose is excreted unchanged. The main metabolite in urine is a conjugate
of 4-hydroxy-2,6-xylidine, accounting for about 70 to 80% of the dose excreted in the
urine. 2,6-xylidine is excreted in the urine in man at a concentration of less than 1% of
the dose. The elimination half-life of lidocaine after plaster application in healthy
volunteers is 7.6 hours. The excretion of lidocaine and its metabolites may be delayed
in cardiac, renal or hepatic insufficiency.

5.3

Preclinical safety data

Effects in non-clinical general toxicity studies were observed only at exposures
considered sufficiently in excess of the maximum human exposure indicating little
relevance to clinical use.
Lidocaine HCl has shown no genotoxicity when investigated in vitro or in vivo. Its
hydrolysis product and metabolite, 2,6-xylidine, showed mixed genotoxic activity in
several assays particularly after metabolic activation.
Carcinogenicity studies have not been performed with lidocaine. Studies performed
with the metabolite 2,6-xylidine mixed in the diet of male and female rats resulted in
treatment-related cytotoxicity and hyperplasia of the nasal olfactory epithelium and
carcinomas and adenomas in the nasal cavity were observed. Tumorigenic changes
were also found in the liver and subcutis. Because the risk to humans is unclear, longterm treatment with high doses of lidocaine should be avoided.

Lidocaine had no effect on general reproductive performance, female fertility or
embryo-foetal development/teratogenicity in rats at plasma concentrations up to more
than 50-fold those observed in patients.
Animal studies are incomplete with respect to male fertility, parturition or postnatal
development.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Self-adhesive layer:
glycerol
liquid sorbitol
carmellose sodium
propylene glycol (E1520)
urea
heavy kaolin
tartaric acid
gelatin
polyvinyl alcohol
aluminium glycinate
disodium edetate
methyl parahydroxybenzoate (E218)
propyl parahydroxybenzoate (E216)
polyacrylic acid
sodium polyacrylate
purified water
Backing fabric:
Polyethylene terephthalate (PET)
Release liner:
Polyethylene terephthalate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.
Shelf life after first opening: 14 days

6.4

Special precautions for storage

Do not refrigerate or freeze.
After first opening: Keep the sachet tightly closed.

6.5

Nature and contents of container

Re-sealable sachet composed of paper/polyethylene/aluminium/ethylene meta-acrylic
acid co-polymer containing 5 plasters.
Each carton contains 5, 10, 20, 25 or 30 plasters. Not all pack sizes may be marketed.

6.6

Special precautions for disposal

After use the plaster still contains active substance. After removal, the used plasters
should be folded in half, adhesive side inwards so that the self-adhesive layer is not
exposed, and the plaster should be discarded.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER

Grünenthal Limited
Regus Lakeside House
1 Furzeground Way
Stockley Park East
Uxbridge
Middlesex UB11 1BD

United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)

PL 21727/0075

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/02/2017

10

DATE OF REVISION OF THE TEXT
22/02/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

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