Qutenza 179 mg cutaneous patch

Each 280 cm² cutaneous patch contains a total of 179 mg of capsaicin or 640 micrograms of capsaicin per cm² of patch (8 % w/w).

Excipient

Each 50 g tube of cleansing gel for Qutenza contains 0.2 mg/g butylhydroxyanisole (E320).

For a full list of excipients, see section 6.1.

Cutaneous patch.

Each patch is 14 cm x 20 cm (280 cm²) and consists of an adhesive side containing the active substance and an outer surface backing layer. The adhesive side is covered with a removable, clear, unprinted, diagonally cut, release liner. The outer surface of the backing layer is imprinted with 'capsaicin 8%'.

Qutenza is indicated for the treatment of peripheral neuropathic pain in non-diabetic adults either alone or in combination with other medicinal products for pain.

Qutenza should be applied to the most painful skin areas (using up to a maximum of 4 patches). The painful area should be determined by the physician and marked on the skin. Qutenza must be applied to intact, non-irritated, dry skin, and allowed to remain in place for 30 minutes for the feet (e.g. HIV-associated neuropathy) and 60 minutes for other locations (e.g. postherpetic neuralgia). Qutenza treatments may be repeated every 90 days, as warranted by the persistence or return of pain.

The Qutenza cutaneous patch should be applied by a physician or by a health care professional under the supervision of a physician.

Nitrile gloves should be worn at all times while handling Qutenza and cleaning treatment areas. Latex gloves should NOT be worn as they do not provide adequate protection.

Patches should not be held near eyes or mucous membranes.

Direct contact with Qutenza, used gauze or used cleansing gel should be avoided.

If necessary, hairs in the affected area should be clipped to promote patch adherence (do not shave). The treatment area(s) should be gently washed with soap and water. Following hair removal and washing, the skin should be thoroughly dried.

The treatment area should be pre-treated with a topical anaesthetic prior to application of Qutenza to reduce application related discomfort. The topical anaesthetic should be applied to cover the entire Qutenza treatment area and surrounding 1 to 2 cm. The topical anaesthetic should be used in accordance with the product's instructions for use. In clinical trials, patients were pre-treated with topical lidocaine (4%) or lidocaine (2.5%)/prilocaine (2.5%) for 60 minutes.

Qutenza is a single use patch and can be cut to match the size and shape of the treatment area. Qutenza should be cut prior to removal of the release liner. The release liner should NOT be removed until just prior to application. There is a diagonal cut in the release liner to aid in its removal. A section of the release liner should be peeled and folded and the adhesive side of the printed patch placed on the treatment area. The patch should be held in place. The release liner should slowly and carefully be peeled from underneath with one hand while the patch should simultaneously be smoothed onto the skin with the other.

To ensure Qutenza maintains contact to the treatment area, stretchable socks or rolled gauze may be used.

The Qutenza patches should be removed gently and slowly by rolling them inward to minimize the risk of aerosolisation of capsaicin. After removal of Qutenza, cleansing gel should be applied liberally to the treatment area and left on for at least one minute. Cleansing gel should be wiped off with dry gauze to remove any remaining capsaicin from the skin. After the cleansing gel has been wiped off, the area should be gently washed with soap and water.

Acute pain during and following the procedure should be treated with local cooling (such as a cool compress) and oral analgesics (e.g., short-acting opioids).

See section 6.6 for the instructions for handling and disposal of the treatment materials.

Patients with renal and/or hepatic impairment

No dose adjustment is required for patients with renal or hepatic impairment.

Paediatric population

Qutenza is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Hypersensitivity to the active substance or to any of the excipients.

Health care professionals should wear nitrile gloves when handling patches and cleansing treatment areas.

Qutenza should be used only on dry, intact (unbroken) skin and not on the face, above the hairline of the scalp, and/or in proximity to mucous membranes.

Care must be taken to avoid unintentional contact with the patches or other materials that have come in contact with the treated areas. Exposure of the skin to capsaicin results in transient erythema and burning sensation, with mucous membranes being particularly susceptible. Inhalation of airborne capsaicin can result in coughing or sneezing. Used patches should be disposed of immediately after use in an appropriate medical waste container (see section 6.6).

If Qutenza comes in contact with skin not intended to be treated, cleansing gel should be applied for one minute and wiped off with dry gauze to remove any remaining capsaicin from the skin surface. After the cleansing gel has been wiped off, the area should be gently washed with soap and water. If burning of eyes, skin, or airway occurs, the affected individual should be removed from the vicinity of Qutenza. Eyes or mucous membranes should be flushed or rinsed with water. Appropriate medical care should be provided if shortness of breath develops.

As a result of treatment-related increases in pain, transient increases in blood pressure (on average < 8.0 mm Hg) may occur during and shortly after the Qutenza treatment. Blood pressure should be monitored during the treatment procedure. Patients experiencing increased pain should be provided with supportive treatment such as local cooling or oral analgesics (i.e., short acting opioids). For patients with unstable or poorly controlled hypertension or a recent history of cardiovascular events, the risk of adverse cardiovascular reactions due to the potential stress of the procedure should be considered prior to initiating Qutenza treatment.

Patients using high doses of opioids may not respond to oral opioid analgesics when used for acute pain during and following the treatment procedure. A thorough history should be reviewed prior to initiating treatment and an alternative pain reduction strategy in place prior to Qutenza treatment in patients with suspected high opioid tolerance.

Though no treatment-related reductions in neurological function have been observed in clinical studies with Qutenza, minor and temporary changes in sensory function (e.g., heat detection) have been reported following administration of capsaicin. Patients with increased risk for adverse reactions due to minor changes in sensory function should be cautious when using Qutenza.

There is only limited experience with Qutenza in patients with Painful Diabetic Neuropathy (PDN). Repeated treatments with Qutenza in patients with PDN have not been studied.

The cleansing gel for Qutenza contains butylhydroxyanisole, which may cause local skin reactions (e.g. contact dermatitis) or irritation of the eyes and mucous membranes.

No formal interaction studies with other medicinal products have been performed as only transient low levels of systemic absorption have been shown to occur with Qutenza.

No clinical data on exposed pregnancies are available.

Studies in animals have not shown teratogenic effects.

Based on human pharmacokinetics, which show transient, low systemic exposure to capsaicin, the likelihood that Qutenza increases the risk of developmental abnormalities when given to pregnant women is very low. However, caution should be exercised when prescribing to pregnant women.

No clinical data on breast-feeding women are available.

Studies in lactating rats exposed to Qutenza everyday for 3 hours showed measurable levels of capsaicin in the mothers' milk. It is unknown whether capsaicin is excreted in human breast milk. As a precautionary measure, it is advisable to not breast-feed on the day of treatment.

No studies on the effects of Qutenza on the ability to drive and use machines have been performed. However, application of Qutenza is unlikely to have any direct effects on the central nervous system, as only very low, transient levels of capsaicin are systemically absorbed and there is no evidence that capsaicin affects cognition, memory or reaction times.

Of the 1,327 patients treated with Qutenza in randomized controlled trials, 883 (67%) reported adverse reactions considered related to the medicinal product by the investigator. The most commonly reported adverse reactions were transient local applications site burning, pain, erythema and pruritus. Adverse reactions were transient, self-limited and usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 0.8% for patients receiving Qutenza and 0.6% for patients receiving control.

In Table 1 below all adverse reactions, which occurred at an incidence greater than control and in more than one patient in controlled clinical trials in patients with PHN and painful HIV-AN, are listed by system organ class and frequency: very common ( 1/10), common ( 1/100 to < 1/10) and uncommon ( 1/1,000 to < 1/100).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Treatment-emergent related adverse reaction incidence in controlled trials

No treatment-related reductions in neurological function, as eva luated by Quantitative Sensory Testing (QST) and neurological examinations, have been observed during clinical studies in patients with peripheral neuropathic pain. Temporary, minor changes in heat detection (1°C to 2°C) and sharp sensations were detected at the Qutenza application site in healthy volunteer studies.

No case of overdose has been reported. Qutenza is required to be administered by a physician or under the supervision of a physician. Therefore, overdosing is unlikely to occur. Overdose may be associated with severe application site reactions, e.g. application site pain, application site erythema, application site pruritus. In case of suspected overdose, the patches should be removed gently, cleansing gel should be applied for one minute and then wiped off with dry gauze and the area should be gently washed with soap and water. Supportive measures should be taken as clinically needed. There is no antidote to capsaicin.

Pharmacotherapeutic group: Other local anaesthetics, ATC code: N01BX04

Mechanism of action

Capsaicin, or 6-nonenamide, N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methyl , (6E), is a highly selective agonist for the transient receptor potential vanilloid 1 receptor (TRPV1). The initial effect of capsaicin is the activation of TRPV1-expressing cutaneous nociceptors, which results in pungency and erythema due to the release of vasoactive neuropeptides.

Pharmacodynamic effects

Following capsaicin exposure, cutaneous nociceptors become less sensitive to a variety of stimuli. These later-stage effects of capsaicin are frequently referred to as “desensitization” and are thought to underlie the pain relief. Sensations from non TRPV1-expressing cutaneous nerves are expected to remain unaltered, including the ability to detect mechanical and vibratory stimuli. Capsaicin-induced alterations in cutaneous nociceptors are reversible and it has been reported and observed that normal function (the detection of noxious sensations) returns within weeks in healthy volunteers.

Clinical Efficacy

Efficacy of a single 30-minute application of Qutenza to the feet has been shown in controlled clinical trials conducted in patients with painful HIV-AN. Efficacy of a single 60-minute application of Qutenza to locations other than the feet has been shown in controlled clinical trials conducted in patients with PHN. Pain reduction was observed as early as week 1 and was maintained throughout the 12-week study period. Qutenza has been shown to be effective when used alone or when used in combination with systemic medicinal products for neuropathic pain.

The capsaicin contained in Qutenza is intended for delivery into the skin. In vitro data (active substance dissolution and skin permeation assays) demonstrate that the rate of release of capsaicin from Qutenza is linear during the application time. Based on in vitro studies, approximately 1% of capsaicin is estimated to be absorbed into the epidermal and dermal layers of skin during one-hour applications. As the amount of capsaicin released from the patch per hour is proportional to the surface area of application, this amounts to an estimated total maximum possible dose for a 1000 cm² area of application of approximately 7 mg. Assuming 1000 cm² of patch area delivers approximately 1% of capsaicin from the patch to a 60 kg person, the maximum potential exposure to capsaicin is approximately 0.12 mg/kg, once every 3 months.

According to the EC Scientific Committee on Food, the average European oral intake of capsaicin is 1.5 mg/day (0.025 mg/kg/day for a 60 kg person) and the highest dietary exposure is 25 to 200 mg/day (up to 3.3 mg/kg/day for a 60 kg person).

Pharmacokinetic data in humans showed transient, low (< 5 ng/ml) systemic exposure to capsaicin in about one third of PHN patients, in 3% of patients with PDN and in no HIV-AN patients following 60-minute applications of Qutenza. No data are available following 30-minute treatments. In general, the proportions of PHN patients with systemic exposure to capsaicin increased with larger treatment areas and with longer treatment durations. The highest concentration of capsaicin detected in patients treated for 60 minutes was 4.6 ng/mL, which occurred immediately after Qutenza removal. Most quantifiable levels were observed at the time of Qutenza removal, with a clear trend towards disappearance by 3 to 6 hours after Qutenza removal. No detectable levels of metabolites were observed in any subject.

A population pharmacokinetic analysis of patients treated for 60 and 90 minutes indicated that capsaicin levels in plasma peaked around 20 minutes after Qutenza removal and declined very rapidly, with a mean elimination half-life of about 130 minutes.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity, and repeated-dose toxicity.

Genotoxicity studies performed with capsaicin show a weak mutagenic response in the mouse lymphoma assay and negative responses in the Ames, mouse micronucleus and chromosomal aberration in human peripheral blood lymphocytes assays.

A carcinogenicity study performed in mice indicates that capsaicin is not carcinogenic.

A reproductive toxicology study conducted in rats showed a statistically significant reduction in the number and percent of motile sperms in rats treated 3 hours/day beginning 28 days before cohabitation, through cohabitation and continuing through the day before sacrifice. Although neither statistically significant nor dose dependent, the Fertility Index and the number of pregnancies per number of rats in cohabitation were reduced in all capsaicin-treated groups.

A teratology study conducted in rabbits did not show any potential for fetotoxicity. Delays in skeletal ossification (reductions in ossified metatarsals) were observed in a rat teratology study at dose levels higher than human therapeutic levels; the significance of this finding in humans is unknown. Peri- and post-natal toxicology studies, conducted in rats do not show potential for reproductive toxicity. Lactating rats exposed to Qutenza daily for 3 hours showed measurable levels of capsaicin in the mothers' milk.

A mild sensitization was seen in a cutaneous sensitization study with guinea pigs.

Patch

Matrix:

silicone adhesives

diethylene glycol monoethyl ether

silicone oil

ethylcellulose N50 (E462)

Backing layer:

polyester backing film

printing ink containing Pigment White 6

Removable protective layer:

polyester release liner

Cleansing gel

macrogol 300

carbomer

purified water

sodium hydroxide (E524)

disodium edetate

butylhydroxyanisole (E320)

Not applicable.

Unopened sachet: 4 years

After opening sachet: apply Qutenza within 2 hours

Qutenza cutaneous patch: Store flat in the original sachet and carton. Store below 25°C.

Cleansing gel: Store below 25°C.

The Qutenza patch is stored in a paper coated aluminium foil sachet with acrylnitrile-acrylic acid copolymer heat seal layer.

Qutenza is available in a kit containing one or two individually sealed Qutenza patches and a 50 g tube of cleansing gel.

Not all pack sizes may be marketed.

Health care professionals should wear nitrile gloves when handling patches and cleansing treatment areas.

Used and unused patches and all other materials that have been in contact with the treated area should be disposed of by sealing them in a polyethylene medical waste bag and placing in an appropriate medical waste container.

Astellas Pharma Europe B.V.

Elisabethhof 19

2353 EW Leiderdorp

Netherlands

EU/1/09/524/001-002

15/05/2009

February 2011