ALDARA 5% cream medication leaflet

ALDARA 5% cream

Each sachet contains 12.5 mg of imiquimod in 250 mg cream (5 %).

100 mg of cream contains 5 mg of imiquimod.

Methyl hydroxybenzoate (E 218) 2.0 mg/g cream

Propyl hydroxybenzoate (E 216) 0.2 mg/g cream

Cetyl alcohol 22.0 mg/g cream

Stearyl alcohol 31.0 mg/g cream

Benzyl alcohol 20.0 mg/g cream

For the full list of excipients, see section 6.1.

Cream.

White to slightly yellow cream.

Imiquimod cream is indicated for the topical treatment of:

* External genital and perianal warts (condylomata acuminata) in adults.

* Small superficial basal cell carcinomas (sBCCs) in adults.

* Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AKs) on the face orscalp in immunocompetent adult patients when size or number of lesions limit the efficacyand/or acceptability of cryotherapy and other topical treatment options are contraindicated orless appropriate.

The application frequency and duration of treatment with imiquimod cream is different for eachindication.

External genital warts in adults:

Imiquimod cream should be applied 3 times per week (example: Monday, Wednesday, and Friday; or

Tuesday, Thursday, and Saturday) prior to normal sleeping hours, and should remain on the skin for6 to 10 hours. Imiquimod cream treatment should continue until the clearance of visible genital orperianal warts or for a maximum of 16 weeks per episode of warts.

For quantity to be applied see section 4.2 Method of administration.

Superficial basal cell carcinoma in adults:

Apply imiquimod cream for 6 weeks, 5 times per week (example: Monday to Friday) prior to normalsleeping hours, and leave on the skin for approximately 8 hours.

For quantity to be applied see 4.2 Method of administration.

Actinic keratosis in adults

Treatment should be initiated and monitored by a physician. Imiquimod cream should be applied3 times per week (example: Monday, Wednesday and Friday) for four weeks prior to normal sleepinghours, and left on the skin for approximately 8 hours. Sufficient cream should be applied to cover thetreatment area. After a 4-week treatment-free period, clearance of AKs should be assessed. If anylesions persist, treatment should be repeated for another four weeks.

The maximum recommended dose is one sachet.

An interruption of dosing should be considered if intense local inflammatory reactions occur (seesection 4.4) or if infection is observed at the treatment site. In this latter case, appropriate othermeasures should be taken. Each treatment period should not be extended beyond 4 weeks due tomissed doses or rest periods.

If the treated area does not show complete clearance at a follow-up examination about 8 weeks afterthe last 4-weeks course of treatment, an additional 4-weeks course of Aldara treatment may beconsidered.

A different therapy is recommended if the treated lesion(s) shows insufficient response to Aldara.

Actinic keratosis lesions that have cleared after one or two courses of treatment and subsequentlyrecur can be re-treated with one or two further courses of Aldara cream following an at least 12 weekstreatment pause (see section 5.1).

Information applicable to all indications:

If a dose is missed, the patient should apply the cream as soon as he/she remember and then he/sheshould continue with the regular schedule. However the cream should not be applied more than once aday.

Use in the paediatric patient population is not recommended. There are no data available on the use ofimiquimod in children and adolescents in the approved indications.

Aldara should not be used in children with molluscum contagiosum due to lack of efficacy in thisindication (see section 5.1).

External genital warts:

Imiquimod cream should be applied in a thin layer and rubbed on the clean wart area until the creamvanishes. Only apply to affected areas and avoid any application on internal surfaces. Imiquimodcream should be applied prior to normal sleeping hours. During the 6 to 10 hour treatment period,showering or bathing should be avoided. After this period it is essential that imiquimod cream isremoved with mild soap and water. Application of an excess of cream or prolonged contact with theskin may result in a severe application site reaction (see sections 4.4, pct. 4.8 and 4.9). A single-use sachetis sufficient to cover a wart area of 20 cm2 (approx. 3 inches2). Sachets should not be re-used onceopened. Hands should be washed carefully before and after application of cream.

Uncircumcised males treating warts under the foreskin should retract the foreskin and wash the areadaily (see section 4.4).

Superficial basal cell carcinoma:

Before applying imiquimod cream, patients should wash the treatment area with mild soap and waterand dry thoroughly. Sufficient cream should be applied to cover the treatment area, including onecentimetre of skin surrounding the tumour. The cream should be rubbed into the treatment area untilthe cream vanishes. The cream should be applied prior to normal sleeping hours and remain on theskin for approximately 8 hours. During this period, showering and bathing should be avoided. Afterthis period it is essential that imiquimod cream is removed with mild soap and water.

Sachets should not be re-used once opened. Hands should be washed carefully before and afterapplication of cream.

Response of the treated tumour to imiquimod cream should be assessed 12 weeks after the end oftreatment. If the treated tumour shows an incomplete response, a different therapy should be used (seesection 4.4).

A rest period of several days may be taken (see section 4.4) if the local skin reaction to imiquimodcream causes excessive discomfort to the patient, or if infection is observed at the treatment site. Inthis latter case, appropriate other measures should be taken.

Actinic keratosis:

Before applying imiquimod cream, patients should wash the treatment area with mild soap and waterand dry thoroughly. Sufficient cream should be applied to cover the treatment area. The cream shouldbe rubbed into the treatment area until the cream vanishes. The cream should be applied prior tonormal sleeping hours and remain on the skin for approximately 8 hours. During this period,showering and bathing should be avoided. After this period it is essential that imiquimod cream isremoved with mild soap and water. Sachets should not be re-used once opened. Hands should bewashed carefully before and after application of cream.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

External genital warts, superficial basal cell carcinoma and actinic keratosis:

Avoid contact with the eyes, lips and nostrils.

Imiquimod has the potential to exacerbate inflammatory conditions of the skin.

Imiquimod cream should be used with caution in patients with autoimmune conditions (refer to section4.5). Consideration should be given to balancing the benefit of imiquimod treatment for these patientswith the risk associated with a possible worsening of their autoimmune condition.

Imiquimod cream should be used with caution in organ transplant patients (refer to section 4.5).

Consideration should be given to balancing the benefit of imiquimod treatment for these patients withthe risk associated with the possibility of organ rejection or graft-versus-host disease.

Imiquimod cream therapy is not recommended until the skin has healed after any previous drug orsurgical treatment. Application to broken skin could result in increased systemic absorption ofimiquimod leading to a greater risk of adverse events (refer to section 4.8 and 4.9)

The use of an occlusive dressing is not recommended with imiquimod cream therapy.

The excipients methyl hydroxybenzoate (E 218) and propyl hydroxybenzoate (E 216) may causeallergic reactions (possibly delayed). Cetyl alcohol and stearyl alcohol may cause local skin reactions(e.g. contact dermatitis). Benzyl alcohol may cause allergic reactions and mild local irritation.

Rarely, intense local inflammatory reactions including skin weeping or erosion can occur after only afew applications of imiquimod cream. Local inflammatory reactions may be accompanied, or evenpreceded, by flu-like systemic signs and symptoms including malaise, pyrexia, nausea, myalgias andrigors. An interruption of dosing should be considered.

Imiquimod should be used with caution in patients with reduced haematologic reserve (refer to section4.8d).

External genital warts:

There is limited experience in the use of imiquimod cream in the treatment of men with foreskin-associated warts. The safety database in uncircumcised men treated with imiquimod cream three timesweekly and carrying out a daily foreskin hygiene routine is less than 100 patients. In other studies, inwhich a daily foreskin hygiene routine was not followed, there were two cases of severe phimosis andone case of stricture leading to circumcision. Treatment in this patient population is thereforerecommended only in men who are able or willing to follow the daily foreskin hygiene routine. Earlysigns of stricture may include local skin reactions (e.g. erosion, ulceration, oedema, induration), orincreasing difficulty in retracting the foreskin. If these symptoms occur, the treatment should bestopped immediately. Based on current knowledge, treating urethral, intra-vaginal, cervical, rectal orintra-anal warts is not recommended. Imiquimod cream therapy should not be initiated in tissueswhere open sores or wounds exist until after the area has healed.

Local skin reactions such as erythema, erosion, excoriation, flaking and oedema are common. Otherlocal reactions such as induration, ulceration, scabbing, and vesicles have also been reported. Shouldan intolerable skin reaction occur, the cream should be removed by washing the area with mild soapand water. Treatment with imiquimod cream can be resumed after the skin reaction has moderated.

The risk of severe local skin reactions may be increased when imiquimod is used at higher thanrecommended doses (see section 4.2). However, in rare cases severe local reactions that have requiredtreatment and/or caused temporary incapacitation have been observed in patients who have usedimiquimod according to the instructions. Where such reactions have occurred at the urethral meatus,some women have experienced difficulty in urinating, sometimes requiring emergency catheterisationand treatment of the affected area.

No clinical experience exists with imiquimod cream immediately following treatment with othercutaneously applied drugs for treatment of external genital or perianal warts. Imiquimod cream shouldbe washed from the skin before sexual activity. Imiquimod cream may weaken condoms anddiaphragms, therefore concurrent use with imiquimod cream is not recommended. Alternative formsof contraception should be considered.

In immunocompromised patients, repeat treatment with imiquimod cream is not recommended.

While limited data have shown an increased rate of wart reduction in HIV positive patients,imiquimod cream has not been shown to be as effective in terms of wart clearance in this patientgroup.

Superficial basal cell carcinoma:

Imiquimod has not been evaluated for the treatment of basal cell carcinoma within 1 cm of the eyelids,nose, lips or hairline.

During therapy and until healed, affected skin is likely to appear noticeably different from normalskin. Local skin reactions are common but these reactions generally decrease in intensity duringtherapy or resolve after cessation of imiquimod cream therapy. There is an association between thecomplete clearance rate and the intensity of local skin reactions (e.g. erythema). These local skinreactions may be related to the stimulation of local immune response. If required by the patient’sdiscomfort or the severity of the local skin reaction, a rest period of several days may be taken.

Treatment with imiquimod cream can be resumed after the skin reaction has moderated.

The clinical outcome of therapy can be determined after regeneration of the treated skin,approximately 12 weeks after the end of treatment.

No clinical experience exists with the use of imiquimod cream in immunocompromised patients.

No clinical experience exists in patients with recurrent and previously treated BCCs, therefore use forpreviously treated tumours is not recommended.

Data from an open label clinical trial suggest that large tumours (>7.25 cm2) are less likely to respondto imiquimod therapy.

The skin surface area treated should be protected from solar exposure.

Actinic keratosis

Lesions clinically atypical for AK or suspicious for malignancy should be biopsied to determineappropriate treatment.

Imiquimod has not been evaluated for the treatment of actinic keratoses on the eyelids, the inside ofthe nostrils or ears, or the lip area inside the vermilion border.

There are very limited data available on the use of imiquimod for the treatment of actinic keratoses inanatomical locations other than the face and scalp. The available data on actinic keratosis on theforearms and hands do not support efficacy in this indication and therefore such use is notrecommended.

Imiquimod is not recommended for the treatment of AK lesions with marked hyperkeratosis orhypertrophy as seen in cutaneous horns.

During therapy and until healed, affected skin is likely to appear noticeably different from normalskin. Local skin reactions are common but these reactions generally decrease in intensity duringtherapy or resolve after cessation of imiquimod cream therapy. There is an association between thecomplete clearance rate and the intensity of local skin reactions (e.g. erythema). These local skinreactions may be related to the stimulation of local immune response. If required by the patient’sdiscomfort or the intensity of the local skin reaction, a rest period of several days may be taken.

Treatment with imiquimod cream can be resumed after the skin reaction has moderated.

Each treatment period should not be extended beyond 4 weeks due to missed doses or rest periods.

The clinical outcome of therapy can be determined after regeneration of the treated skin,approximately 4-8 weeks after the end of treatment.

No clinical experience exists with the use of imiquimod cream in immunocompromised patients.

Information on re-treating actinic keratosis lesions that have cleared after one or two courses oftreatment and subsequently recur is given in section 4.2 and 5.1.

Data from an open-label clinical trial suggest that subjects with more than 8 AK lesions showed adecreased rate of complete clearance compared to patients with less than 8 lesions.

The skin surface area treated should be protected from solar exposure.

No interaction studies have been performed. This includes studies with immunosuppressive drugs.

Interactions with systemic drugs would be limited by the minimal percutaneous absorption ofimiquimod cream.

Due to its immunostimulating properties, imiquimod cream should be used with caution in patientswho are receiving immunosuppressive medication (see section 4.4).

For imiquimod no clinical data on exposed pregnancies are available. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturitionor postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnantwomen.

As no quantifiable levels (> 5 ng/ml) of imiquimod are detected in the serum after single and multipletopical doses, no specific advice can be given on whether to use or not in lactating mothers.

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

a) General Description:

External genital warts:

In the pivotal trials with 3 times a week dosing, the most frequently reported adverse drug reactionsjudged to be probably or possibly related to imiquimod cream treatment were application site reactionsat the wart treatment site (33.7% of imiquimod treated patients). Some systemic adverse reactions,including headache (3.7%), influenza-like symptoms (1.1%), and myalgia (1.5%) were also reported.

Patient reported adverse reactions from 2292 patients treated with imiquimod cream in placebocontrolled and open clinical studies are presented below. These adverse events are considered at leastpossibly causally related to treatment with imiquimod.

Superficial basal cell carcinoma:

In trials with 5 times per week dosing 58% of patients experienced at least one adverse event. Themost frequently reported adverse events from the trials judged probably or possibly related toimiquimod cream are application site disorders, with a frequency of 28.1%. Some systemic adversereactions, including back pain (1.1%) and influenza-like symptoms (0.5%) were reported byimiquimod cream patients.

Patient reported adverse reactions from 185 patients treated with imiquimod cream in placebocontrolled phase III clinical studies for superficial basal cell carcinoma are presented below. Theseadverse events are considered at least possibly causally related to treatment with imiquimod.

Actinic keratosis

In the pivotal trials with 3 times per week dosing for up to 2 courses each of 4 weeks, 56% ofimiquimod patients reported at least one adverse event. The most frequently reported adverse eventfrom these trials judged probably or possibly related to imiquimod cream was application sitereactions (22% of imiquimod treated patients). Some systemic adverse reactions, including myalgia(2%) were reported by imiquimod treated patients.

Patient reported adverse reactions from 252 patients treated with imiquimod cream in vehiclecontrolled phase III clinical studies for actinic keratosis are presented below. These adverse events areconsidered at least possibly causally related to treatment with imiquimod.

b) Tabular Listing of adverse events:

Frequencies are defined as Very common (1/10), Common (1/100 to <1/10) and Uncommon(1/1,000 to <1/100). Lower frequencies from clinical trials are not reported here.

External genital Superficial basal Actinic keratosiswarts cell carcinoma(3x/ wk,16wks) (5x/wk, 6 wks) (3x/wk, 4 or 8 wks)

N = 2292 N = 185 N = 252

Infection Common Common Uncommon

Pustules Common Uncommon

Herpes simplex Uncommon

Genital candidiasis Uncommon

Vaginitis Uncommon

Bacterial infection Uncommon

Fungal infection Uncommon

Upper respiratory tract infection Uncommon

Vulvitis Uncommon

Rhinitis Uncommon

Influenza Uncommon

Blood and lymphatic systemdisorders:

Lymphadenopathy Uncommon Common Uncommon

Anorexia Uncommon Common

Insomnia Uncommon

Depression Uncommon Uncommon

Irritability Uncommon

Headache Common Common

Paraesthesia Uncommon

Dizziness Uncommon

Migraine Uncommon

Somnolence Uncommon

Conjunctival irritation Uncommon

Eyelid oedema Uncommon

Ear and labyrinth disorders:

Tinnitus Uncommon

Flushing Uncommon

Respiratory, thoracic andmediastinal disorders:

Pharyngitis Uncommon

Rhinitis Uncommon

Nasal congestion Uncommon

Pharyngo laryngeal pain Uncommon

Nausea Common Uncommon Common

Abdominal pain Uncommon

Diarrhoea Uncommon Uncommon

Vomiting Uncommon

Rectal disorder Uncommon

Rectal tenesmus Uncommon

Dry mouth Uncommon

Skin and subcutaneous tissuedisorders:

Pruritus Uncommon

Dermatitis Uncommon Uncommon

Folliculitis Uncommon

Rash erythematous Uncommon

Eczema Uncommon

Rash Uncommon

Sweating increased Uncommon

Urticaria Uncommon

Actinic keratosis Uncommon

Erythema Uncommon

Face oedema Uncommon

Skin ulcer Uncommon

Musculoskeletal and connectivetissue disorders:

Myalgia Common Common

Arthralgia Uncommon Common

Back pain Uncommon Common

Pain in extremity Uncommon

Dysuria Uncommon

Reproductive system and breastdisorders:

Genital pain male Uncommon

Penile disorder Uncommon

Dyspareunia Uncommon

Erectile dysfunction Uncommon

Uterovaginal prolapse Uncommon

Vaginal pain Uncommon

Vaginitis atrophic Uncommon

Vulval disorder Uncommon

General disorders andadministration site conditions:

Application site pruritus Very common Very common Very common

Application site pain Very common Common Common

Application site burning Common Common Common

Application site irritation Common Common Common

Application site erythema Common Common

Application site reaction Common

Application site bleeding Common Uncommon

Application site papules Common Uncommon

Application site paraesthesia Common Uncommon

Application site rash Common

Fatigue Common Common

Pyrexia Uncommon Uncommon

Influenza-like illness Uncommon Uncommon

Pain Uncommon

Asthenia Uncommon Uncommon

Malaise Uncommon

Rigors Uncommon Uncommon

Application site dermatitis Uncommon

Application site discharge Uncommon Uncommon

Application site hyperaesthesia Uncommon

Application site inflammation Uncommon

Application site oedema Uncommon Uncommon

Application site scabbing Uncommon Uncommon

Application site scar Uncommon

Application site skin breakdown Uncommon

Application site swelling Uncommon Uncommon

Application site ulcer Uncommon

Application site vesicles Uncommon Uncommon

Application site warmth Uncommon

Lethargy Uncommon

Discomfort Uncommon

Inflammation Uncommonc) Frequently occurring adverse events:

External genital warts:

Investigators of placebo controlled trials were required to evaluate protocol mandated clinical signs(skin reactions). These protocol mandated clinical sign assessments indicate that local skin reactionsincluding erythema (61%), erosion (30%), excoriation/flaking/scaling (23%) and oedema (14%) werecommon in these placebo controlled clinical trials with imiquimod cream applied three times weekly(see section 4.4). Local skin reactions, such as erythema, are probably an extension of thepharmacologic effects of imiquimod cream.

Remote site skin reactions, mainly erythema (44%), were also reported in the placebo controlled trials.

These reactions were at non-wart sites which may have been in contact with imiquimod cream. Mostskin reactions were mild to moderate in severity and resolved within 2 weeks of treatmentdiscontinuation. However, in some cases these reactions have been severe, requiring treatment and/orcausing incapacitation. In very rare cases, severe reactions at the urethral meatus have resulted indysuria in women (see section 4.4).

Superficial basal cell carcinoma:

Investigators of the placebo controlled clinical trials were required to evaluate protocol mandatedclinical signs (skin reactions). These protocol mandated clinical sign assessments indicate that severeerythema (31%) severe erosions (13%) and severe scabbing and crusting (19%) were very common inthese trials with imiquimod cream applied 5 times weekly. Local skin reactions, such as erythema, areprobably an extension of the pharmacologic effect of imiquimod cream.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have notresulted, the possibility of infection in broken skin should always be considered.

Actinic keratosis

In clinical trials of imiquimod cream 3 times weekly for 4 or 8 weeks the most frequently occurringapplication site reactions were itching at the target site (14%) and burning at the target site (5%).

Severe erythema (24%) and severe scabbing and crusting (20%) were very common. Local skinreactions, such as erythema, are probably an extension of the pharmacologic effect of imiquimodcream. See 4.2 and 4.4 for information on rest periods.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have notresulted, the possibility of infection in broken skin should always be considered.

d) Adverse events applicable to all indications:

Reports have been received of localised hypopigmentation and hyperpigmentation followingimiquimod cream use. Follow-up information suggests that these skin colour changes may bepermanent in some patients. In a follow-up of 162 patients five years after treatment for sBCC a mildhypopigmentation was observed in 37% of the patients and a moderate hypopigmentation wasobserved in 6% of the patients. 56% of the patients have been free of hypopigmentation;hyperpigmentation has not been reported.

Clinical studies investigating the use of imiquimod for the treatment of actinic keratosis have detecteda 0.4% (5/1214) frequency of alopecia at the treatment site or surrounding area. Postmarketing reportsof suspected alopecia occurring during the treatment of sBCC and EGW have been received.

Reductions in haemoglobin, white blood cell count, absolute neutrophils and platelets have beenobserved in clinical trials. These reductions are not considered to be clinically significant in patientswith normal haematologic reserve. Patients with reduced haematologic reserve have not been studiedin clinical trials. Reductions in haematological parameters requiring clinical intervention have beenreported from postmarketing experience. There have been postmarketing reports of elevated liverenzymes.

Rare reports have been received of exacerbation of autoimmune conditions.

Rare cases of remote site dermatologic drug reactions, including erythema multiforme, have beenreported from clinical trials. Serious skin reactions reported from postmarketing experience includeerythema multiforme, Stevens Johnson syndrome and cutaneous lupus erythematosus.

e) Paediatric population:

Imiquimod was investigated in controlled clinical studies with paediatric patients (see sections 4.2 and5.1). There was no evidence for systemic reactions. Application site reactions occurred morefrequently after imiquimod than after vehicle, however, incidence and intensity of these reactions werenot different from that seen in the licensed indications in adults. There was no evidence for seriousadverse reaction caused by imiquimod in paediatric patients.

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.

When applied topically, systemic overdosage with imiquimod cream is unlikely due to minimalpercutaneous absorption. Studies in rabbits reveal a dermal lethal dose of greater than 5 g/kg.

Persistent dermal overdosing of imiquimod cream could result in severe local skin reactions.

Following accidental ingestion, nausea, emesis, headache, myalgia and fever could occur after a singledose of 200 mg imiquimod which corresponds to the content of approximately 16 sachets. The mostclinically serious adverse event reported following multiple oral doses of  200 mg was hypotensionwhich resolved following oral or intravenous fluid administration.

Pharmacotherapeutic group: Chemotherapeutics for topical use, antivirals, ATC Code: D06BB10

Imiquimod is an immune response modifier. Saturable binding studies suggest a membrane receptorfor imiquimod exists on responding immune cells. Imiquimod has no direct antiviral activity. Inanimal models imiquimod is effective against viral infections and acts as an antitumour agentprincipally by induction of alpha interferon and other cytokines. The induction of alpha interferon andother cytokines following imiquimod cream application to genital wart tissue has also beendemonstrated in clinical studies.

Increases in systemic levels of alpha interferon and other cytokines following topical application ofimiquimod were demonstrated in a pharmacokinetic study.

External genital warts:

Clinical Efficacy

The results of 3 phase III pivotal efficacy studies showed that treatment with imiquimod for sixteenweeks was significantly more effective than treatment with vehicle as measured by total clearance oftreated warts.

In 119 imiquimod-treated female patients, the combined total clearance rate was 60% as compared to20% in 105 vehicle-treated patients (95% CI for rate difference: 20% to 61%, p<0.001). In thoseimiquimod patients who achieved total clearance of their warts, the median time to clearance was8 weeks.

In 157 imiquimod-treated male patients, the combined total clearance rate was 23% as compared to5% in 161 vehicle-treated patients (95%CI for rate difference: 3% to 36%, p<0.001). In thoseimiquimod patients who achieved total clearance of their warts, the median time to clearance was12 weeks.

Superficial basal cell carcinoma:

The efficacy of imiquimod 5 times per week for 6 weeks was studied in two double-blind vehiclecontrolled clinical trials. Target tumours were histologically confirmed single primary superficial basalcell carcinomas with a minimum size of 0.5 cm2 and a maximum diameter of 2 cm. Tumours locatedwithin 1 cm of the eyes, nose, mouth, ears or hairline were excluded. In a pooled analysis of these twostudies, histological clearance was noted in 82% (152/185) of patients. When clinical assessment wasalso included, clearance judged by this composite endpoint was noted in 75% (139/185) of patients.

These results were statistically significant (p<0.001) by comparison with the vehicle group, 3%(6/179) and 2% (3/179) respectively. There was a significant association between the intensity of localskin reactions (e.g. erythema) seen during the treatment period and complete clearance of the basalcell carcinoma.

Five -year data from a long-term open-label uncontrolled study indicate that an estimated 77.9%[95% CI (71.9%, 83.8%)] of all the subjects who initially received treatment became clinically clearand remained clear at 60 months.

Actinic keratosis:

The efficacy of imiquimod applied 3 times per week for one or two courses of 4 weeks, separated by a4 week treatment-free period, was studied in two double-blind vehicle controlled clinical trials.

Patients had clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions on thebalding scalp or face within a contiguous 25 cm2 treatment area. 4-8 AK lesions were treated. Thecomplete clearance rate (imiquimod minus placebo) for the combined trials was 46.1% (CI 39.0%,53.1%).

One-year data from two combined observational studies indicate a recurrence rate of 27%(35/128 patients) in those patients who became clinically clear after one or two courses of treatment.

The recurrence rate for individual lesions was 5.6% (41/737). Corresponding recurrence rates forvehicle were 47% (8/17 patients) and 7.5% (6/80 lesions).

Two open-label, randomised, controlled clinical trials compared the long-term effects of imiquimodwith those of topical diclofenac in patients with actinic keratosis with respect to the risk of progressionto in situ or invasive squamous cell carcinoma (SCC). Treatments were given as officiallyrecommended. If the treated AK field was not completely cleared of lesions, additional treatmentcycles could be started. All patients were followed-up until withdrawal or up to 3 years afterrandomisation. Results are emerged from a meta-analysis of both trials.

A total of 482 patients were included into the trials, of these 481 patients received study treatments,and of these 243 patients were treated with imiquimod and 238 patients with topical diclofenac. Thetreated AK field was located on the balding scalp or face with a contiguous area of about 40 cm² forboth treatment groups presenting with a median number of 7 clinically typical AK lesions at baseline.

There is clinical experience from 90 patients who got 3 or more imiquimod treatment cycles, 80patients received 5 or more courses of imiquimod treatment over the 3-year study period.

Regarding the primary endpoint, histological progression, overall 13 of 242 patients (5.4%) of theimiquimod group and 26 of 237 patients (11.0%) of the diclofenac group were found to have ahistological progression to in situ or invasive SCC within 3 years, a difference of -5.6% (95% CI:

- 10.7% to -0.7%). Thereof 4 of 242 patients (1.7%) of the imiquimod and 7 of 237 patients (3.0%) ofthe diclofenac group were found to have a histological progression to invasive SCC within the 3-yearperiod.

A total of 126 of 242 patients treated with imiquimod (52.1%) and 84 of 237 patients treated withtopical diclofenac (35.4%) showed complete clinical clearance of the treated AK field at week 20 (i.e.

about 8 weeks after the end of the initial treatment cycle); a difference of 16.6% (95% CI: 7.7% to25.1%). For those patients with complete clinical clearance of the treated AK field recurrence of AKlesions was evaluated. A patient was counted as recurrent in these trials if at least one AK lesion wasobserved in the completely cleared field whereby a recurrent lesion could be a lesion which occurredat the same location as a formerly cleared lesion or a newly identified lesion anywhere in the treated

AK field. The risk for recurrence of AK lesions in the treated field (as defined above) was 39.7% (50of 126 patients) until month 12 for patients treated with imiquimod compared with 50.0% (42 of 84patients) for patients treated with topical diclofenac, a difference of -10.3% (95% CI: -23.6% to 3.3%);and 66.7% (84 of 126 patients) for a treatment with imiquimod and 73.8% (62 of 84 patients) fortopical diclofenac until month 36, a difference of -7.1% (95% CI: -19.0% to 5.7%).

A patient with recurrent AK lesions (as defined above) in the completely cleared field had a chance ofabout 80% to become completely cleared again following an additional imiquimod treatment cyclecompared with a chance of about 50% for a re-treatment with topical diclofenac.

The approved indications genital warts, actinic keratosis and superficial basal cell carcinoma areconditions not generally seen within the paediatric population and were not studied.

Aldara Cream has been evaluated in four randomised, vehicle controlled, double-blind trials inchildren aged 2 to 15 years with molluscum contagiosum (imiquimod n = 576, vehicle n = 313). Thesetrials failed to demonstrate efficacy of imiquimod at any of the tested dosage regimens (3x/weekfor ≤16 weeks and 7x/week for ≤8 weeks).

External genital warts, superficial basal cell carcinoma and actinic keratosis:

Less than 0.9% of a topically applied single dose of radiolabelled imiquimod was absorbed throughthe skin of human subjects. The small amount of drug which was absorbed into the systemiccirculation was promptly excreted by both urinary and faecal routes at a mean ratio of approximately3 to 1. No quantifiable levels (>5 ng/ml) of drug were detected in serum after single or multiple topicaldoses.

Systemic exposure (percutaneous penetration) was calculated from recovery of carbon-14 from 14Cimiquimod in urine and faeces.

Minimal systemic absorption of imiquimod 5% cream across the skin of 58 patients with actinickeratosis was observed with 3 times per week dosing for 16 weeks. The extent of percutaneousabsorption did not change significantly between the first and last doses of this study. Peak serum drugconcentrations at the end of week 16 were observed between 9 and 12 hours and were 0.1, 0.2, and1.6 ng/mL for the applications to face (12.5 mg, 1 single-use sachet), scalp (25 mg, 2 sachets) andhands/arms (75 mg, 6 sachets), respectively. The application surface area was not controlled in thescalp and hands/ arms groups. Dose proportionality was not observed. An apparent half-life wascalculated that was approximately 10 times greater than the 2 hour half-life seen followingsubcutaneous dosing in a previous study, suggesting prolonged retention of drug in the skin. Urinaryrecovery was less than 0.6% of the applied dose at week 16 in these patients.

The pharmacokinetic properties of imiquimod following single and multiple topical application inpaediatric patients with molluscum contagiosum (MC) have been investigated. The systemic exposuredata demonstrated that the extent of absorption of imiquimod following topical application to the MClesional skin of the paediatric patients aged 6-12 years was low and comparable to that observed inhealthy adults and adults with actinic keratosis or superficial basal cell carcinoma. In younger patientsaged 2-5 years absorption, based on Cmax values, was higher compared to adults.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, mutagenicity and teratogenicity.

In a four-month rat dermal toxicity study, significantly decreased body weight and increased spleenweight were observed at 0.5 and 2.5 mg/kg; similar effects were not seen in a four month mousedermal study. Local dermal irritation, especially at higher doses, was observed in both species.

A two-year mouse carcinogenicity study by dermal administration on three days a week did not inducetumours at the application site. However, the incidences of hepatocellular tumours among treatedanimals were greater than those for controls. The mechanism for this is not known, but as imiquimodhas low systemic absorption from human skin, and is not mutagenic, any risk to humans from systemicexposure is likely to be low. Furthermore, tumours were not seen at any site in a 2-year oralcarcinogenicity study in rats.

Imiquimod cream was evaluated in a photocarcinogenicity bioassay in albino hairless mice exposed tosimulated solar ultraviolet radiation (UVR). Animals were administered imiquimod cream three timesper week and were irradiated 5 days per week for 40 weeks. Mice were maintained for an additional12 weeks for a total of 52 weeks. Tumours occurred earlier and in greater number in the group of miceadministered the vehicle cream in comparison with the low UVR control group. The significance forman is unknown. Topical administration of imiquimod cream resulted in no tumour enhancement atany dose, in comparison with the vehicle cream group.

isostearic acidbenzyl alcoholcetyl alcoholstearyl alcoholwhite soft paraffinpolysorbate 60sorbitan stearateglycerolmethyl hydroxybenzoate (E 218)propyl hydroxybenzoate (E 216)xanthan gumpurified water.

Not applicable.

2 years.

Do not store above 25 °C.

Sachets should not be re-used once opened.

Boxes of 12 or 24 single-use polyester/aluminium foil sachets, containing 250 mg of cream.

Not all pack sizes may be marketed.

No special requirements.

Viatris Healthcare Limited

Damastown Industrial Park

Mulhuddart

Dublin 15

DUBLIN

Ireland

EU/1/98/080/001-002

Date of first authorisation: 18/09/1998

Date of last renewal: 03/09/2008

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

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