FORTACIN 150mg / 50mg / ml skin spray solution medication leaflet

Fortacin 150 mg/ml + 50 mg/ml cutaneous spray, solution

Each ml of solution contains 150 mg lidocaine and 50 mg prilocaine.

Each actuation delivers 50 microlitres which contains 7.5 mg lidocaine and 2.5 mg prilocaine.

1 dose is equal to 3 actuations.

For the full list of excipients, see section 6.1.

Cutaneous spray, solution

Colourless to light yellow solution

Fortacin is indicated for the treatment of primary premature ejaculation in adult men.

The recommended dose is 3 actuations applied to cover the glans penis. Each dose consists of a totalof 22.5 mg lidocaine and 7.5 mg prilocaine per application (1 dose is equal to 3 actuations).

A maximum of 3 doses can be used within 24 hours with at least 4 hours between doses.

Dose adjustments are not required in the elderly (see section 5.1).

Clinical studies have not been performed in patients with impaired renal function, however due to itsmethod of administration and very low systemic absorption, no dosage adjustment is required.

Clinical studies have not been performed in patients with impaired hepatic function, however due to itsmethod of administration and very low systemic absorption, no dosage adjustment is required. Cautionis advised in case of severe hepatic impairment (see section 4.4).

There is no relevant use of Fortacin in the paediatric population for the indication of treatment ofprimary premature ejaculation.

Cutaneous use.

Fortacin is only indicated for application to the glans penis.

Before initial use, the spray container should be briefly shaken and then primed by spraying it into theair three times.

Before each subsequent use, it should be briefly shaken and then the spray container should bere-primed by spraying into the air once.

Any foreskin should be retracted from the glans penis. The spray container should be held in anupright position before use. Fortacin should be applied to the entire glans penis, by actuating the valve3 times. One third of the glans penis should be covered with each actuation. After 5 minutes anyexcess spray should be wiped off prior to intercourse.

Hypersensitivity of the patient or their partner to the active substances or to any of the excipients listedin section 6.1.

Patients or their partner with a known history of sensitivity to local anaesthetics of the amide type.

Precautions for use

Premature ejaculation may be due to a condition requiring medical supervision. If this product used asdirected does not provide relief, the patient should discontinue use and seek medical advice.

Avoid contact with the eyes and ears

When applied in the vicinity of the eyes, Fortacin may cause eye irritation. Also the loss of protectivereflexes may allow corneal irritation and potential abrasion. If eye contact occurs, the eye shouldimmediately be rinsed with water or sodium chloride solution and protected until sensation returns.

When applied to an impaired tympanic membrane, Fortacin may cause ototoxicity of the middle ear.

Risk of injury

Fortacin sprayed onto mucous membranes of the patient or their partner, such as the mouth, nose andthroat, or transferred onto female genitalia or anal lining, could be absorbed and temporary localnumbness/anaesthesia is likely to result. This hypoaesthesia may mask normal pain sensations and,therefore, increase the dangers of localised injury.

Use with condoms

Fortacin must not be used with polyurethane-based female and male condoms as deterioration wasobserved and protection from sexually transmitted diseases or pregnancy may be reduced. Fortacin canbe used with contraceptive devices made of latex rubber, polyisoprene, nitrile and silicone as nodeterioration has been shown with these materials.

A higher rate of erectile dysfunction and male genital hypoaesthesia may be experienced when using

Fortacin with male condoms.

Anaemia related conditions

Patients or their partner with glucose-6-phosphate dehydrogenase deficiency or congenital oridiopathic methaemoglobinaemia are more susceptible to medicinal product-inducedmethaemoglobinaemia (see section 4.5).

Although the systemic availability of prilocaine by cutaneous absorption of Fortacin is low, cautionshould be exercised in patients with anaemia, congenital or acquired methaemoglobinaemia or patientson concomitant therapy known to produce such conditions.

Hypersensitivities

Patients allergic to paraaminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have notshown cross sensitivity to lidocaine and/or prilocaine; however, Fortacin should be used with cautionin patients with a history (or partner with a history) of sensitivities to medicinal products, especially ifthe aetiologic medicinal product is uncertain.

Skin effects

In case the patient or their partner develop a rash or skin irritation, treatment with Fortacin should bediscontinued. If symptoms persist, the patient should consult a doctor.

Patients with severe hepatic impairment

Patients with severe hepatic disease, because of their inability to metabolise local anaestheticsnormally, are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine (seesection 4.2).

Methaemoglobinaemia may be accentuated in patients already taking medicinal products known toinduce the condition, e.g. sulphonamides, acetanilid, aniline dyes, benzocaine, chloroquine, dapsone,metoclopramide, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside,pamaquine, para-aminosalicylic acid, phenobarbital, phenytoin, primaquine and quinine (seesection 4.4).

The risk of additional systemic toxicity should be considered when large doses of Fortacin are appliedto patients already using other local anaesthetics or structurally related medicinal products, e.g. class Ianti-arrhythmics such as mexiletine.

Specific interaction studies with lidocaine/prilocaine and anti-arrhythmic medicinal products class III(e.g. amiodarone) have not been performed, but caution is advised due to the potential increase ofantiarrhythmic effect.

Medicinal products that inhibit cytochrome P450 (CYP) 1A2 reduce the clearance of lidocaine (e.g.

fluvoxamine, cimetidine or betablockers) and may cause potentially toxic plasma concentrations whenlidocaine is given intravenously in repeated high doses over a long time period (30 hours).

Fortacin is not indicated for use by women. However, there may be some exposure in female partnersof men treated with Fortacin.

Women of childbearing potential/contraception in male and females

Patients hoping to achieve conception should either avoid using Fortacin, or, if it is essential toachieve penetration, should wash the glans penis as thoroughly as possible 5 minutes after applyingthe spray but prior to intercourse.

There are no or limited amount of data from the use of lidocaine and prilocaine in pregnant women.

Animal studies do not indicate reproductive toxicity (see section 5.3). As a precautionary measure, it ispreferable to avoid the use of Fortacin during pregnancy unless effective male barrier contraceptivemeasures are taken in order to avoid potential foetal exposure.

Lidocaine and prilocaine are excreted in human milk, but at therapeutic doses of Fortacin no effects onthe breastfed newborns/infants are anticipated due to active substance transfer from the male patient tohis female partner. Fortacin can be used during breast-feeding if clinically needed.

There are no adequate data from the use of lidocaine and prilocaine on fertility in humans. A study inrats showed that Fortacin caused a reduction in sperm motility (see section 5.3). This medicinalproduct may reduce the possibility of pregnancy, but should not be used as a contraceptive.

Fortacin has no or negligible influence on the ability to drive and use machines.

The most frequent adverse reactions reported with the use of this medicinal product in male patientswere local effects of genital hypoaesthesia (4.5%) and erectile dysfunction (4.4%). These adversereactions caused discontinuation of treatment in 0.2% and 0.5% of patients, respectively.

The most frequent adverse reactions reported with the use of this medicinal product in female partnerswere vulvovaginal burning sensation (3.9%), and genital hypoaesthesia (1.0%). Vulvovaginaldiscomfort or burning sensation caused discontinuation of treatment in 0.3% of subjects.

Frequency of the adverse reactions is 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). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Adverse drug reactions in male glans-penis-treated subjects

System organ class Frequency Adverse reactions

Psychiatric disorders Uncommon Abnormal orgasm

Nervous system disorders Uncommon Headache

Respiratory, thoracic and Uncommon Throat irritationmediastinal disorders

Skin and subcutaneous tissue Uncommon Skin irritationdisorders

Adverse drug reactions in male glans-penis-treated subjects

System organ class Frequency Adverse reactions

Reproductive system and breast Common Hypoaesthesia of male genital,disorders Erectile dysfunction,

Genital burning sensation

Uncommon Genital erythema,

Ejaculation failure,

Paraesthesia of male genital,

Penile pain,

Penis disorder,

Pruritus genital

General disorders and Uncommon Pyrexiaadministration site conditions

Adverse drug reactions in sexual partners

System Organ Class Frequency Adverse Reactions

Infections and infestations Uncommon Vaginal candidiasis

Nervous system disorders Uncommon Headache

Respiratory, thoracic and Uncommon Throat irritationmediastinal disorders

Gastrointestinal disorders Uncommon Anorectal discomfort,

Oral parasthesia

Renal and urinary disorders Uncommon Dysuria

Reproductive system and breast Common Vulvovaginal burning sensation,disorders Hypoaesthesia

Uncommon Vulvovaginal discomfort,

Vaginal pain,

Vulvovaginal pruritus

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

It is unlikely that Fortacin at the recommended dosages to result in an overdose.

However, should symptoms of systemic toxicity occur, the signs are anticipated to be similar in natureto those following the administration of local anaesthetics by other routes. Local anaesthetic toxicity ismanifested by symptoms of nervous system excitation (e.g. restlessness, vertigo, hearing and visualdisorders, nausea, vomiting, tremor and muscle twitching) and, in severe cases, central nervous andcardiovascular depression (e.g hypotension, bradycardia and circulatory collapse which may lead tocardiac arrest).

Severe neurological symptoms (convulsions, CNS depression) must be treated symptomatically byrespiratory support and the administration of anticonvulsive medicinal products.

Prilocaine in high doses may cause an increase in the methaemoglobin level particularly inconjunction with methaemoglobin-inducing medicinal products (e.g. sulphonamides). Clinicallysignificant methaemoglobinaemia should be treated with a slow intravenous injection ofmethylthioninium chloride.

Pharmacotherapeutic group: Anaesthetics, amides, ATC code: N01BB20

Fortacin provides topical anaesthesia to the glans penis. The active substances lidocaine and prilocaineblock the transmission of nerve impulses in the glans penis, reducing the sensitivity of the glans penis.

This is translated into a delaying of the ejaculatory latency time without adversely affecting thesensation of ejaculation.

Clinical studies have shown Fortacin to increase the intra-vaginal ejaculatory latency time (IELT),increase control over ejaculation and reduce the feelings of distress in patients with prematureejaculation as measured by the Index of Premature Ejaculation (IPE). The medicinal product has arapid onset of action and is effective within 5 minutes of application. The effectiveness of themedicinal product has been demonstrated to persist on repeat use over time.

The efficacy of Fortacin was demonstrated in two multi-centre, multinational, randomised,double-blind, placebo controlled studies (PSD502-PE-002 and PSD502-PE-004) both followed by anopen-label phase. Men satisfying the International Society for Sexual Medicine (ISSM) criteria forpremature ejaculation (PE) who had a baseline IELT ≤ 1 minutes in at least 2 of the first 3 sexualencounters during screening were eligible to enrol.

The ITT population for the two combined pivotal studies comprised 539 patients, with 358 and 181patients in the Fortacin and placebo groups, respectively (2:1 ratio) for the initial, three month DBphase. The Per Protocol population comprised 430 patients (284 and 146 patients in the Fortacin andplacebo groups, respectively).

Demographic characteristics for the ITT population of PSD502-PE-002 and PSD502-PE-004individually are summarised in table below.

Demographics: ITT population (PSD502-PE-002 and PSD502-PE-004 individual results)

PSD502-PE-002 PSD502-PE-004

PSD502 Placebo Total PSD502 Placebo Total

Demographic N = 167 N = 82 N = 249 N = 191 N = 99 N = 290

Age (years)n 167 82 249 191 99 290

Mean 39.1 37.9 38.7 34.6 35.2 34.8

SD 11.71 11.97 11.97 9.56 11.20 10.13

Range 18 - 67 18 - 68 18 - 68 19 - 65 20 - 60 19 - 65

Median 39.0 36.0 38.0 33.0 33.0 33.0

Age group (years)18 to < 25 1214 (8.4%) 26 (10.4) 27 (14.1%) 19 (19.2%) 46 (15.9%)(14.6%)25 to < 35 53 26 11879 (31.7) 82 (42.9%) 36 (36.4%)(31.7%) (31.7%) (40.7%)35 to < 45 44 1862 (24.9) 50 (26.2%) 20 (20.2%) 70 (24.1%)(26.3%) (22.0%)45 to < 55 39 1857 (22.9) 24 (12.6%) 19 (19.2%) 43 (14.8%)(23.4%) (22.0%)55 to < 65 13 (7.8%) 7 (8.5%) 20 ( 8.0) 7 (3.7%) 5 (5.1%) 12 (4.1%)≥ 65 4 (2.4%) 1 (1.2%) 5 ( 2.0) 1 (0.5%) 0 1 (0.3%)

Race/ethnic origin

Caucasian 133 74 207 188 99 (100%) 287(79.6%) (90.2%) (83.1%) (98.4%) (99.0%)

Afro- 17 1 (0.5%) 0 1 (0.3%)4 (4.9%) 21 (8.4%)

American/Caribbean (10.2%)

Hispanic 9 (5.4%) 2 (2.4%) 11 (4.4%) 0 0 0

Asian 5 (3.0%) 2 (2.4%) 7 (2.8%) 1 (0.5%) 0 1 (0.3%)

Other 3 (1.8%) 0 3 (1.2%) 1 (0.5%) 0 1 (0.3%)

Abbreviations: BMI = body mass index; ITT = intention-to-treat; SD = standard deviation

The effectiveness of Fortacin in treating PE was assessed by measuring IELT and the co primaryendpoints of ejaculatory control, sexual satisfaction, and distress using the IPE. During the 3 monthsof the double-blind treatment phase, the geometric mean IELT increased from 0.58 to 3.17 minutes inthe Fortacin group and from 0.56 to 0.94 minutes in the placebo group.

85.2% of subjects in the Fortacin group achieved a mean IELT of > 1 minute over the course of3 months of treatment with it, whereas 46.4% of the placebo subjects had a mean IELT of > 1 minute.

66.2% of Fortacin-treated subjects and 18.8% of placebo-treated subjects achieved a mean IELT> 2 minutes.

The clinically significant increases in IELT were paralleled by significant differences in the IPE scores(p < 0.0001). Adjusted mean change scores (Fortacin vs. placebo) at Month 3 were 8.2 vs. 2.2 for theejaculatory control score, 7.2 vs. 1.9 for the sexual satisfaction score, and 3.7 vs. 1.1 for the distressscore.

In Fortacin-treated subjects, IELT and IPE scores increased at the first measured timepoint. Both IELTand IPE scores continued to increase slightly more throughout the remainder of the double-blind phase.

The positive changes in IELT and IPE domain scores were maintained during the open-labeltreatment phase.

At each of the three monthly assessments all subjects completed a Premature Ejaculation Profile (PEP)questionnaire relating to perceived control over ejaculation, personal distress related to ejaculation,satisfaction with sexual intercourse, and interpersonal difficulty relating to ejaculation. The PEP scoresfollowed a similar pattern of improvement to the IELT and IPE scores. For all of the three monthlyassessments completed by the subjects, there was a significant difference between Fortacin and placebo(p < 0.0001). Partners completed the PEP questionnaire at month three. There was also a significantdifference over placebo in all domains for the responses from the partners (p < 0.0001).

Patients recruited into the clinical trials ranged from 18- 68 years of age. In the pivotal clinical studies,subgroup analysis of the efficacy response in different age groups showed that the efficacy and safetyprofiles were quite consistent between the different age groups.

There is a large safety database for lidocaine and prilocaine, due to their established use. This does notindicate a safety concern for elderly

The European Medicines Agency has waived the obligation to submit the results of studies with

Fortacin in all subsets of the paediatric population in primary premature ejaculation (see section 4.2for information on paediatric use).

The plasma levels of lidocaine and prilocaine in male and female subjects were below the levelassociated with toxicity (5 000 ng/ml). Male volunteers had maximum plasma concentrations oflidocaine which were less than 4% of toxic levels, and prilocaine which were less than 0.4% of toxiclevels, after repeat dosing. Female volunteers receiving repeated doses directly to the cervix andvagina of up to five times the recommended dose for the male partner, had maximum plasma levels oflidocaine which were less than 8% of toxic levels, and prilocaine which were less than 1% of toxiclevels.

Systemic exposure to lidocaine and prilocaine and their metabolites (respectively 2,6-xylidine ando-toluidine), is low following application to the glans penis in male patients and application to thecervix/vagina fornices in female subjects, at doses higher than recommended.

Lidocaine

The steady-state volume of distribution is 1.1 to 2.1 L/kg after intravenous administration. Lidocaineis reported to be 66% bound by plasma proteins, including alpha-1-acid glycoprotein. Lidocaine cancross the blood brain barrier and the placenta and is distributed in breast milk.

Prilocaine

Following intravenous administration, the steady state volume of distribution of prilocaine is 0.7 to4.4 L/kg. Prilocaine is reported to be 55% bound to plasma proteins, including alpha-1-acidglycoprotein. Prilocaine crosses the blood-brain barrier and also crosses the placenta. Prilocaine is alsodistributed in breast milk.

Lidocaine is largely metabolised in the liver by cytochrome P450 (CYP 3A4) and probably to a minorextent in the skin. First pass metabolism is rapid and extensive and bioavailability is about 35% afteroral doses.

Prilocaine is rapidly metabolised in both the liver, by cytochrome P450, and in the kidneys byamidases.

The metabolism of lidocaine and prilocaine results in the formation of 2,6-xylidine and o-toluidine,respectively, amongst other metabolites. Plasma levels of these metabolites detected afteradministration of Fortacin in clinical trials were low in both male and female subjects, even after dosesof it many times in excess of the clinical dose were applied. No 2,6-xylidine or o-toluidine wasdetectable at any time-point in vaginal fluids following local application of the medicinal product infemale volunteers.

Lidocaine

The terminal elimination half-life of lidocaine from the plasma following intravenous administration isapproximately 65 - 150 minutes and the systemic clearance is 10 - 20 mL/min/kg. Lidocaine isexcreted in the urine mainly as metabolites, with only a small proportion excreted unchanged.

Prilocaine

The elimination half-life of prilocaine following intravenous administration is approximately10 - 150 minutes. The systemic clearance is 18 - 64 mL/min/kg. Prilocaine is excreted in the urinemainly as its metabolites, with only a small proportion excreted unchanged.

Lidocaine

No teratogenic effects were observed in studies of embryonic/foetal development in rats and rabbitsreceiving doses during organogenesis. Embryotoxicity was observed in rabbits at doses toxic to themother. The postnatal survival time of the offspring of rats treated during pregnancy and lactation witha dose toxic to the mother was shown to be reduced.

Prilocaine

In a study of pregnant rats receiving a combination of lidocaine and prilocaine during organogenesis,no effects on embryonic/foetal development were observed. There are however no systemic exposuredata available for comparison with clinical exposure.

Lidocaine

Lidocaine was not genotoxic and the carcinogenic potential of lidocaine has not been studied. Thelidocaine metabolite 2,6-xylidine has genotoxic potential in vitro. In a carcinogenicity study of ratsexposed to 2,6-xylidine in utero, postnatally and throughout their lifetime, tumours in the nasal cavity,subcutaneous tumours and liver tumours were observed. The clinical relevance of tumour findings inrelation to short-term/intermittent use of lidocaine in humans is unknown. Human exposure from

Fortacin is 20-30 fold less than the minimum dose that did not result in tumours and 200 fold less thanthe minimum dose that did result in tumours.

Prilocaine

Prilocaine was not genotoxic and the carcinogenic potential of prilocaine has not been studied. Theprilocaine metabolite o-toluidine has genotoxic potential in vitro. In carcinogenicity studies ofo-toluidine in rats, mice and hamsters, tumours were observed in several organs. The clinicalrelevance of tumour findings in respect of short-term/intermittent use of prilocaine in humans isunknown. Human exposure is 1 000 fold less than than the minimum dose studied. Note, this dose didresult in tumours.

Effect on fertility

In an in vitro study of rats Fortacin has shown a reduction in sperm motility when 22.5 mg lidocaineand 7.5 mg prilocaine (i.e. the amount in 1 human dose) was in direct contact with rat sperm. Howeverthis study did not reproduce the circumstances of clinical use, as the concentration of Fortacin in directcontact with the sperm would be many fold lower. The potential for reduction of sperm motilityfollowing the clinical use of the medicinal product can not be excluded; therefore it is not possible tostate whether Fortacin would prevent pregnancy.

Norflurane

Deterioriation was observed when Fortacin was used with polyurethane-based female and malecondoms (see section 4.4). Patients should be advised to use alternative methods of contraception.

18 months.

After first use: 12 weeks

Store below 25 °C. Do not freeze.

Aluminium spray container with metering valve.

The metering valve’s components are the stainless steel, POM, TPE, polypropylene, chlorobutylrubber and HDPE.

Each pack contains one spray container with 6.5 ml or 5 ml solution.

Each spray container of 6.5 ml delivers a minimum of 20 doses (1 dose is equal to 3 actuations).

Each spray container of 5 ml delivers a minimum of 12 doses (1 dose is equal to 3 actuations).

The metal container is pressurised. It should not be punctured, broken or burnt, even when apparentlyempty.

A residual volume of fluid that is not usable will remain in the container after all doses have beenadministered.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Recordati Ireland Limited

Raheens East

Ringaskiddy Co. Cork P43 KD30

Ireland

EU/1/13/881/001

EU/1/13/881/002

Date of first authorisation: 15 November 2013

Date of latest renewal: 15 September 2023

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Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu