imiquimod: prescribing information – dosing, contraindications, interactions, side effects

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 or scalp in immunocompetent adult patients when size or number of lesions limit the efficacy and/or acceptability of cryotherapy and other topical treatment options are contraindicated or less appropriate.

Posology

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

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 for 6 to 10 hours. Imiquimod cream treatment should continue until the clearance of visible genital or perianal 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 normal sleeping 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 applied 3 times per week (example: Monday, Wednesday and Friday) for four weeks prior to normal sleeping hours, and left on the skin for approximately 8 hours. Sufficient cream should be applied to cover the treatment area. After a 4-week treatment-free period, clearance of AKs should be assessed. If any lesions 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 (see section 4.4) or if infection is observed at the treatment site. In this latter case, appropriate other measures should be taken. Each treatment period should not be extended beyond 4 weeks due to missed doses or rest periods.

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

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 subsequently recur can be re-treated with one or two further courses of Aldara cream following an at least 12 weeks treatment 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/she should continue with the regular schedule. However the cream should not be applied more than once a day.

Paediatric population
Use in the paediatric patient population is not recommended. There are no data available on the use of imiquimod in children and adolescents in the approved indications.
Aldara should not be used in children with molluscum contagiosum due to lack of efficacy in this indication (see section 5.1).

Method of administration

External genital warts:

Imiquimod cream should be applied in a thin layer and rubbed on the clean wart area until the cream vanishes. Only apply to affected areas and avoid any application on internal surfaces. Imiquimod cream 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 is removed with mild soap and water. Application of an excess of cream or prolonged contact with the skin may result in a severe application site reaction (see sections 4.4, 4.8 and 4.9). A single-use sachet is sufficient to cover a wart area of 20 cm2 (approx. 3 inches2). Sachets should not be re-used once opened. 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 area daily (see section 4.4).

Superficial basal cell carcinoma:

Before applying imiquimod cream, patients should wash the treatment area with mild soap and water and dry thoroughly. Sufficient cream should be applied to cover the treatment area, including one centimetre of skin surrounding the tumour. The cream should be rubbed into the treatment area until the cream vanishes. The cream should be applied prior to normal 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 is removed with mild soap and water.
Sachets should not be re-used once opened. Hands should be washed carefully before and after application of cream.

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

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

Actinic keratosis:

Before applying imiquimod cream, patients should wash the treatment area with mild soap and water and dry thoroughly. Sufficient cream should be applied to cover the treatment area. The cream should be rubbed into the treatment area until the cream vanishes. The cream should be applied prior to normal 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 is removed with mild soap and water. Sachets should not be re-used once opened. Hands should be washed carefully before and after application of cream.

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

a)
General Description:

External genital warts:

In the pivotal trials with 3 times a week dosing, the most frequently reported adverse drug reactions judged to be probably or possibly related to imiquimod cream treatment were application site reactions at 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 placebo controlled and open clinical studies are presented below. These adverse events are considered at least possibly 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. The most frequently reported adverse events from the trials judged probably or possibly related to imiquimod cream are application site disorders, with a frequency of 28.1%. Some systemic adverse reactions, including back pain (1.1%) and influenza-like symptoms (0.5%) were reported by imiquimod cream patients.
Patient reported adverse reactions from 185 patients treated with imiquimod cream in placebo controlled phase III clinical studies for superficial basal cell carcinoma are presented below. These adverse 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% of imiquimod patients reported at least one adverse event. The most frequently reported adverse event from these trials judged probably or possibly related to imiquimod cream was application site reactions (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 vehicle controlled phase III clinical studies for actinic keratosis are presented below. These adverse events are considered 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 warts
(3x/ wk,16wks)
N = 2292
Superficial basal cell carcinoma
(5x/wk, 6 wks)
N = 185
Actinic keratosis

(3x/wk, 4 or 8 wks)
N = 252
Infections and infestations:

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 system disorders:

Lymphadenopathy
Uncommon
Common
Uncommon
Metabolism and nutrition disorders:
Anorexia
Uncommon

Common
Psychiatric disorders:
Insomnia
Uncommon

Depression
Uncommon
Uncommon
Irritability

Uncommon

Nervous system disorders:
Headache
Common

Common
Paraesthesia
Uncommon
Dizziness
Uncommon

Migraine
Uncommon
Somnolence
Uncommon

Eye disorders
Conjunctival irritation

Uncommon
Eyelid oedema
Uncommon
Ear and labyrinth disorders:

Tinnitus
Uncommon
Vascular disorders:

Flushing
Uncommon

Respiratory, thoracic and mediastinal disorders:

Pharyngitis
Uncommon

Rhinitis
Uncommon
Nasal congestion

Uncommon
Pharyngo laryngeal pain
Uncommon
Gastrointestinal disorders:

Nausea
Common
Uncommon
Common
Abdominal pain
Uncommon

Diarrhoea
Uncommon
Uncommon
Vomiting
Uncommon

Rectal disorder
Uncommon
Rectal tenesmus
Uncommon

Dry mouth
Uncommon
Skin and subcutaneous tissue disorders:

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 connective tissue disorders:

Myalgia
Common
Common
Arthralgia
Uncommon
Common
Back pain
Uncommon
Common
Pain in extremity
Uncommon
Renal and urinary disorders:
Dysuria
Uncommon
Reproductive system and breast disorders:

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 and administration 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
Uncommon

c)
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 reactions including erythema (61%), erosion (30%), excoriation/flaking/scaling (23%) and oedema (14%) were common 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 the pharmacologic 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. Most skin reactions were mild to moderate in severity and resolved within 2 weeks of treatment discontinuation. However, in some cases these reactions have been severe, requiring treatment and/or causing incapacitation. In very rare cases, severe reactions at the urethral meatus have resulted in dysuria in women (see section 4.4).

Superficial basal cell carcinoma:

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

Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, 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 occurring application 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 skin reactions, such as erythema, are probably an extension of the pharmacologic effect of imiquimod cream. See 4.2 and 4.4 for information on rest periods.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, 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 following imiquimod cream use. Follow-up information suggests that these skin colour changes may be permanent in some patients. In a follow-up of 162 patients five years after treatment for sBCC a mild hypopigmentation was observed in 37% of the patients and a moderate hypopigmentation was observed 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 detected a 0.4% (5/1214) frequency of alopecia at the treatment site or surrounding area. Postmarketing reports of 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 been observed in clinical trials. These reductions are not considered to be clinically significant in patients with normal haematologic reserve. Patients with reduced haematologic reserve have not been studied in clinical trials. Reductions in haematological parameters requiring clinical intervention have been reported from postmarketing experience. There have been postmarketing reports of elevated liver enzymes.

Rare reports have been received of exacerbation of autoimmune conditions.

Rare cases of remote site dermatologic drug reactions, including erythema multiforme, have been reported from clinical trials. Serious skin reactions reported from postmarketing experience include erythema 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 and 5.1). There was no evidence for systemic reactions. Application site reactions occurred more frequently after imiquimod than after vehicle, however, incidence and intensity of these reactions were not different from that seen in the licensed indications in adults. There was no evidence for serious adverse reaction caused by imiquimod in paediatric patients.

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 the national reporting system listed in Appendix V.

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 section 4.5). Consideration should be given to balancing the benefit of imiquimod treatment for these patients with 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 with the 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 or surgical treatment. Application to broken skin could result in increased systemic absorption of imiquimod 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 cause allergic 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 a few applications of imiquimod cream. Local inflammatory reactions may be accompanied, or even preceded, by flu-like systemic signs and symptoms including malaise, pyrexia, nausea, myalgias and rigors. An interruption of dosing should be considered.

Imiquimod should be used with caution in patients with reduced haematologic reserve (refer to section 4.8d).

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 times weekly and carrying out a daily foreskin hygiene routine is less than 100 patients. In other studies, in which a daily foreskin hygiene routine was not followed, there were two cases of severe phimosis and one case of stricture leading to circumcision. Treatment in this patient population is therefore recommended only in men who are able or willing to follow the daily foreskin hygiene routine. Early signs of stricture may include local skin reactions (e.g. erosion, ulceration, oedema, induration), or increasing difficulty in retracting the foreskin. If these symptoms occur, the treatment should be stopped immediately. Based on current knowledge, treating urethral, intra-vaginal, cervical, rectal or intra-anal warts is not recommended. Imiquimod cream therapy should not be initiated in tissues where open sores or wounds exist until after the area has healed.

Local skin reactions such as erythema, erosion, excoriation, flaking and oedema are common. Other local reactions such as induration, ulceration, scabbing, and vesicles have also been reported. Should an intolerable skin reaction occur, the cream should be removed by washing the area with mild soap and 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 than recommended doses (see section 4.2). However, in rare cases severe local reactions that have required treatment and/or caused temporary incapacitation have been observed in patients who have used imiquimod according to the instructions. Where such reactions have occurred at the urethral meatus, some women have experienced difficulty in urinating, sometimes requiring emergency catheterisation and treatment of the affected area.

No clinical experience exists with imiquimod cream immediately following treatment with other cutaneously applied drugs for treatment of external genital or perianal warts. Imiquimod cream should be washed from the skin before sexual activity. Imiquimod cream may weaken condoms and diaphragms, therefore concurrent use with imiquimod cream is not recommended. Alternative forms of 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 patient group.

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 normal skin. Local skin reactions are common but these reactions generally decrease in intensity during therapy or resolve after cessation of imiquimod cream therapy. There is an association between the complete clearance rate and the intensity of local skin reactions (e.g. erythema). These local skin reactions may be related to the stimulation of local immune response. If required by the patient’s discomfort 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 for previously treated tumours is not recommended.

Data from an open label clinical trial suggest that large tumours (>7.25 cm2) are less likely to respond to 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 determine appropriate treatment.

Imiquimod has not been evaluated for the treatment of actinic keratoses on the eyelids, the inside of the 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 in anatomical locations other than the face and scalp. The available data on actinic keratosis on the forearms and hands do not support efficacy in this indication and therefore such use is not recommended.

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

During therapy and until healed, affected skin is likely to appear noticeably different from normal skin. Local skin reactions are common but these reactions generally decrease in intensity during therapy or resolve after cessation of imiquimod cream therapy. There is an association between the complete clearance rate and the intensity of local skin reactions (e.g. erythema). These local skin reactions may be related to the stimulation of local immune response. If required by the patient’s discomfort 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 of treatment 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 a decreased 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 of imiquimod cream.

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

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

Breast-feeding
As no quantifiable levels (> 5 ng/ml) of imiquimod are detected in the serum after single and multiple topical 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.

When applied topically, systemic overdosage with imiquimod cream is unlikely due to minimal percutaneous 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 single dose of 200 mg imiquimod which corresponds to the content of approximately 16 sachets. The most clinically serious adverse event reported following multiple oral doses of  200 mg was hypotension which resolved following oral or intravenous fluid administration.

5.
PHARMACOLOGICAL PROPERTIES

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

Imiquimod is an immune response modifier. Saturable binding studies suggest a membrane receptor for imiquimod exists on responding immune cells. Imiquimod has no direct antiviral activity. In animal models imiquimod is effective against viral infections and acts as an antitumour agent principally by induction of alpha interferon and other cytokines. The induction of alpha interferon and other cytokines following imiquimod cream application to genital wart tissue has also been demonstrated in clinical studies.

Increases in systemic levels of alpha interferon and other cytokines following topical application of imiquimod 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 sixteen weeks was significantly more effective than treatment with vehicle as measured by total clearance of treated warts.

In 119 imiquimod-treated female patients, the combined total clearance rate was 60% as compared to 20% in 105 vehicle-treated patients (95% CI for rate difference: 20% to 61%, p<0.001). In those imiquimod patients who achieved total clearance of their warts, the median time to clearance was 8 weeks.

In 157 imiquimod-treated male patients, the combined total clearance rate was 23% as compared to 5% in 161 vehicle-treated patients (95%CI for rate difference: 3% to 36%, p<0.001). In those imiquimod patients who achieved total clearance of their warts, the median time to clearance was 12 weeks.

Superficial basal cell carcinoma:

Clinical efficacy:

The efficacy of imiquimod 5 times per week for 6 weeks was studied in two double-blind vehicle controlled clinical trials. Target tumours were histologically confirmed single primary superficial basal cell carcinomas with a minimum size of 0.5 cm2 and a maximum diameter of 2 cm. Tumours located within 1 cm of the eyes, nose, mouth, ears or hairline were excluded. In a pooled analysis of these two studies, histological clearance was noted in 82% (152/185) of patients. When clinical assessment was also 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 local

skin reactions (e.g. erythema) seen during the treatment period and complete clearance of the basal cell 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 clear and remained clear at 60 months.

Actinic keratosis:

Clinical efficacy:

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 through the skin of human subjects. The small amount of drug which was absorbed into the systemic circulation was promptly excreted by both urinary and faecal routes at a mean ratio of approximately 3 to 1. No quantifiable levels (>5 ng/ml) of drug were detected in serum after single or multiple topical doses.

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 actinic keratosis was observed with 3 times per week dosing for 16 weeks. The extent of percutaneous absorption did not change significantly between the first and last doses of this study. Peak serum drug concentrations at the end of week 16 were observed between 9 and 12 hours and were 0.1, 0.2, and 1.6 ng/mL for the applications to face (12.5 mg, 1 single-use sachet), scalp (25 mg, 2 sachets) and hands/arms (75 mg, 6 sachets), respectively. The application surface area was not controlled in the scalp and hands/ arms groups. Dose proportionality was not observed. An apparent half-life was calculated that was approximately 10 times greater than the 2 hour half-life seen following subcutaneous dosing in a previous study, suggesting prolonged retention of drug in the skin. Urinary recovery was less than 0.6% of the applied dose at week 16 in these patients.

Paediatric population

Zyclara is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic, visible or palpable actinic keratosis (AK) of the full face or balding scalp in immunocompetent adults when other topical treatment options are contraindicated or less appropriate.

Posology

Zyclara (per application: up to 2 sachets, 250 mg imiquimod cream per sachet) should be applied once daily before bedtime to the skin of the affected treatment field (area) for two treatment cycles of 2 weeks each separated by a 2-week no-treatment cycle or as directed by the physician.

The treatment area is the full face or balding scalp.

Local skin reactions in the treatment area are in part anticipated and common due to its mode of action (see section 4.4). A rest period of several days may be taken if required by the patient’s discomfort or severity of the local skin reaction. However, neither 2-week treatment cycle should be extended due to missed doses or rest periods.

A transient increase in actinic keratosis counts may be observed during treatment due to the likely effect of imiquimod to reveal and treat subclinical lesions. Response to treatment cannot be adequately assessed until resolution of local skin reactions. Patients should continue treatment as prescribed.
Treatment should be continued for the full treatment course even if all actinic keratosis appear to be gone.

The clinical outcome of therapy has to be determined after regeneration of the treated skin, approximately 8 weeks after the end of treatment and on appropriate intervals thereafter based on clinical judgment. Lesions that do not respond completely to treatment at 8 weeks after the second treatment cycle should be carefully re-evaluated and one additional 2-week treatment of Zyclara may be considered.
A different therapy is recommended if the treated lesion(s) show(s) insufficient response to Zyclara.
Actinic keratosis lesions that have cleared after two Zyclara treatment cycles of 2 weeks and subsequently recur can be re-treated with one or two further Zyclara treatment cycles of 2 weeks following an at least 12 weeks treatment pause.

Hepatic or renal impairment
Patients with hepatic or renal impairment were not included in clinical trials. These patients should be monitored under the close supervision of an experienced physician.

Paediatric population
The safety and efficacy of imiquimod in actinic keratosis in children and adolescents below the age of 18 years have not been established. No data are available.

Method of administration
Zyclara is for external use only. Contact with eyes, lips, and nostrils should be avoided.
The treatment area should not be bandaged or otherwise occluded.
The prescriber should demonstrate the proper application technique to the patient to maximise the benefit of Zyclara therapy.

Zyclara should be applied once daily before bedtime to the skin of the affected treatment field (area) and remain on the skin for approximately 8 hours. During this period, showering and bathing should be avoided. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly. Zyclara should be applied as a thin film to the entire treatment area and rubbed in until the cream vanishes. Up to 2 sachets of Zyclara may be applied to the treatment area (full face or scalp, but not both) at each daily application. Partially-used sachets should be discarded and not reused. Zyclara should be left on the skin for approximately 8 hours; after this time it is essential that the cream is removed by washing the area and the hands with mild soap and water.

Hands should be washed carefully before and after application of cream.

Missed dose
In case a dose is missed, patients should wait until the forthcoming night to apply Zyclara and then continue with the regular schedule. The cream should not be applied more than once daily. Each treatment cycle should not be extended beyond 2 weeks due to missed doses or rest periods.

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

Summary of the safety profile:
The data described below reflect exposure to Zyclara or vehicle in 319 subjects enrolled in two double-blind studies. Subjects applied up to two sachets of Zyclara 3.75% cream or vehicle daily to the skin of the affected area (either entire face or balding scalp, but not both) for two 2-week treatment cycles separated by a 2-week no-treatment cycle.

In clinical trials most patients (159/160) using Zyclara for the treatment of AK experience local skin reactions (most frequently erythema, scab, and exfoliation/application site dryness) at the application site. However, only 11% (17/160) of patients in clinical trials with Zyclara required rest periods (treatment interruption) due to local adverse reactions. Some systemic adverse reactions, including headache 6% (10/160), fatigue 4% (7/160), were reported by Zyclara treated patients in clinical trials.

Tabulated list of adverse reactions
Data presented in the table below reflects:
- exposure to Zyclara or vehicle in above mentioned studies (frequencies very common to uncommon and at greater frequency after vehicle).
- experience with imiquimod 5% cream

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) and not known (cannot be estimated from the available data)

System organ class

Frequency
Adverse reactions
Infections and infestations
Common
Herpes simplex
Uncommon

Infection
Pustules
Frequency not known
Skin infection

Blood and lymphatic system disorders
Common
Lymphadenopathy
Frequency not known

Haemoglobin decreased
White blood cell count decreased
Neutrophil count decreased
Platelet count decreased
Immune system disorders
Rare
Exacerbation of autoimmune conditions
Metabolism and nutrition disorders
Common
Anorexia
Blood glucose increased
Psychiatric disorders
Common
Insomnia
Uncommon
Depression
Irritability
Nervous system disorders
Common
Headache
Dizziness
Eye disorders
Uncommon
Conjunctival irritation
Eyelid oedema
Respiratory, thoracic and mediastinal disorders
Uncommon
Nasal congestion
Pharyngo laryngeal pain
Hepatobiliary disorders
Frequency not known
Hepatic enzyme increased
Gastrointestinal disorders
Common
Nausea
Diarrhoea
Vomiting
Uncommon
Dry mouth
Abdominal pain
Skin and subcutaneous tissue disorders
Very common
Erythema
Scab
Skin exfoliation
Skin oedema
Skin ulcer
Skin hypopigmentation
Common
Dermatitis
Uncommon
Face oedema
Rare
Remote site dermatologic reaction
Frequency not known
Alopecia
Erythema multiforme
Stevens Johnson syndrome
Cutaneous lupus erythematosus

Skin hyperpigmentation
Musculoskeletal and connective tissue disorders
Common
Myalgia
Arthralgia
Uncommon
Back pain
Pain in extremity
General disorders and administration site conditions
Very common
Application site erythema
Application site scabbing
Application site exfoliation
Application site dryness
Application site oedema
Application site ulcer
Application site discharge
Common
Application site reaction
Application site pruritus
Application site pain
Application site swelling
Application site burning
Application site irritation
Application site rash
Fatigue
Pyrexia
Influenza-like illness
Pain
Chest pain
Uncommon
Application site dermatitis
Application site bleeding
Application site papules
Application site paraesthesia
Application site hyperaesthesia
Application site inflammation
Application site scar
Application site skin breakdown
Application site vesicles
Application site warmth
Asthenia
Chills
Lethargy
Discomfort
Inflammation

Description of selected adverse reactions

Blood system disorders
Reductions in haemoglobin, white blood cell count, absolute neutrophils and platelets have been observed in clinical trials investigating the use of imiquimod 5% cream. These reductions are not considered to be clinically significant in patients with normal haematologic reserve. Patients with reduced haematologic reserve have not been studied in clinical trials. Reductions in haematological parameters requiring clinical intervention have been reported from postmarketing experience.

Skin infections
Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, the possibility of infection in broken skin should always be considered.

Hypopigmentation and hyperpigmentation
Reports have been received of localised hypopigmentation and hyperpigmentation following imiquimod 5 % cream use. Follow-up information suggests that these skin colour changes may be permanent in some patients.

Remote site dermatologic reactions
Rare cases of remote site dermatologic reactions, including erythema multiforme, have been reported from clinical trials with imiquimod 5% cream therapy.

Alopecia
Clinical studies investigating the use of imiquimod 5% cream for the treatment of actinic keratosis have detected a 0.4% (5/1214) frequency of alopecia at the treatment site or surrounding area.

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 the national reporting system listed in Appendix V.

General instructions for treatment
Lesions clinically atypical for AK or suspicious for malignancy should be biopsied to determine appropriate treatment.
Contact with eyes, lips and nostrils should be avoided as imiquimod has not been evaluated for the treatment of actinic keratosis on the eyelids, the inside of the nostrils or ears, or the lip area inside the vermilion border.

Imiquimod cream therapy is not recommended until the skin has healed after any previous medicinal products or surgical treatment. Application to broken skin could result in increased systemic absorption of imiquimod leading to a greater risk of adverse events (see section 4.8 and 4.9).
Because of concern for heightened sunburn susceptibility, use of sunscreen is encouraged, and patients should minimise or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Zyclara. The skin surface area treated should be protected from solar exposure.
Imiquimod is not recommended for the treatment of AK lesions with marked hyperkeratosis or hypertrophy as seen in cutaneous horns.

Local skin reactions
During therapy and until healed, affected skin is likely to appear noticeably different from normal skin. Local skin reactions are common but these reactions generally decrease in intensity during therapy or resolve after cessation of imiquimod cream therapy. Rarely, intense local inflammatory reactions including skin weeping or erosion can occur after only a few applications of imiquimod cream.
There is an association between the complete clearance rate and the intensity of local skin reactions (e.g. erythema). These local skin reactions may be related to the stimulation of local immune response.
Furthermore, imiquimod has the potential to exacerbate inflammatory conditions of the skin. If required by the patient’s discomfort 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. The intensity of the local skin reactions tend to be lower in the second cycle than in the first treatment cycle with Zyclara.

Systemic reactions
Flu-like systemic signs and symptoms may accompany, or even precede, intense local skin reactions and may include fatigue, nausea, fever, myalgias, arthralgias, and chills. An interruption of dosing or dose adjustment should be considered (see section 4.8).
Patients with reduced haematologic reserve should be monitored under the close supervision of an experienced physician (see section 4.8).

Special populations
Patients with cardiac, hepatic or renal impairment were not included in clinical trials. These patients should be monitored under the close supervision of an experienced physician.

Use in immunocompromised patients and/or in patients with autoimmune conditions
The safety and efficacy of Zyclara in immunocompromised patients (e.g. organ transplant patients) and/or patients with autoimmune conditions have not been established. Therefore, imiquimod cream should be used with caution in these patients (see section 4.5). Consideration should be given to balancing the benefit of imiquimod treatment for these patients with the risk associated either with the possibility of organ rejection or graft-versus-host disease or a possible worsening of their autoimmune condition.

Re-treatment
Information on re-treating actinic keratosis lesions that have cleared after two Zyclara treatment cycles of 2 weeks and subsequently recur is given in section 4.2 and 5.1.

Excipients
Stearyl alcohol and cetyl alcohol may cause local skin reactions (e.g. contact dermatitis). Benzyl alcohol may cause allergic reactions and mild local irritation.
Methyl parahydroxybenzoate (E 218), and propyl parahydroxybenzoate (E 216) may cause allergic reactions (possibly delayed).

No interaction studies have been performed. This includes studies with immunosuppressive medicinal products. Interactions with systemic medicinal products would be limited by the minimal percutaneous absorption of imiquimod cream.

Due to its immunostimulating properties, imiquimod cream should be used with caution in patients who are receiving immunosuppressive medicinal products (see section 4.4).

Concomitant use of Zyclara and any other imiquimod creams in the same treatment area should be avoided since they contain the same active ingredient (imiquimod) and may increase the risk for and severity of local skin reactions.

Pregnancy
For imiquimod no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see section 5.3).
Caution should be exercised when prescribing Zyclara to pregnant women. Zyclara should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding
It is unknown whether imiquimod/metabolites are excreted in human milk.
A risk to the newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zyclara therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility
No clinical data are available, potential risk for human is unknown.

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

When applied topically, systemic overdose with imiquimod cream is unlikely due to minimal percutaneous absorption. Studies in rabbits reveal a dermal lethal imiquimod dose of greater than 5 g/kg. Persistent topical overdosing of imiquimod cream could result in severe local skin reactions and may increase the risk for systemic reactions.
Following accidental ingestion, nausea, emesis, headache, myalgia and fever could occur after a single dose of 200 mg imiquimod which corresponds to the content of more than 21 sachets of Zyclara. The most clinically serious adverse event reported following multiple oral doses of  200 mg was hypotension which resolved following oral or intravenous fluid administration.

Management of overdose should consist of treatment of clinical symptoms.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, antivirals, ATC Code: D06BB10

Pharmacodynamic effects
Imiquimod is an immune response modifier. It is the lead compound of the imidazoline family.
Saturable binding studies suggest membrane receptors for imiquimod exists on responding cells; these are called toll-like receptor 7 and 8. Imiquimod induces the release of interferon alpha (IFN-α) and other cytokines from a variety of human and animal cells (e.g. from human monocytes/macrophages and keratinocytes). Topical in vivo application of imiquimod cream on mouse skin resulted in increased concentrations of IFN and tumour necrosis factor (TNF) compared with skin of untreated mice. The panel of induced cytokines varies with the cell’s tissue origin. In addition, release of cytokines was induced following dermal application and oral administration of imiquimod in various laboratory animals and in human studies. In animal models imiquimod is effective against viral infections and acts as an antitumour agent principally by inducing release of alpha interferon and other cytokines.

Increases in systemic levels of alpha interferon and other cytokines following topical application of imiquimod were also observed in human data.

Clinical efficacy and safety

The efficacy of Zyclara was studied in two double-blind, randomized, vehicle-controlled clinical studies. Patients had 5-20 typical visible or palpable AK lesions in an area that exceeded 25 cm2 on either the face or balding scalp. 319 subjects with AK were treated with up to 2 sachets once daily of imiquimod 3.75% cream, or a matching vehicle cream for two treatment cycles of 2 weeks separated by a 2-week no-treatment cycle. For the combined trials the complete clearance rate of the full face or balding scalp under imiquimod 3.75% cream was 35.6% (57/160 patients, CI 28.2%, 43.6 %) under vehicle 6.3% (10/159 patients, CI 3.1%, 11.3%) at the 8-week post-treatment visit. No overall differences in safety or effectiveness were observed between patients 65 years or older and the younger patients. Squamous cell carcinoma (SCC) was reported in 1.3% (2/160) of patients treated with imiquimod 3.75%, in 0.6% (1/159) treated with vehicle. This difference was not statistically significant.

In a follow-up study where initially cleared patients with imiquimod 3.75% were followed for at least 14 months without any further AK-treatment, 40.5% of the patients showed sustained complete clearance of the whole treatment area (either full face or scalp) There are no data for imiquimod 3.75% on long-term clearance beyond that.

Absorption
Less than 0.9% of a topically applied single dose of radiolabelled imiquimod was absorbed through the skin of human subjects.
Systemic exposure (percutaneous penetration) was calculated from recovery of carbon-14 from [14C] imiquimod in urine and faeces.
During a pharmacokinetic study with imiquimod 3.75% cream following application of 2 sachets once daily (18.75 mg imiquimod/day) for up to three weeks to the entire face and/or scalp (approximately 200 cm2), low systemic absorption of imiquimod was observed in patients with AK. Steady-state levels were achieved in 2 weeks and time to maximal concentrations (Tmax) ranged between 6 and 9 hours after last application.

Distribution
The mean peak serum imiquimod concentration at the end of the pharmacokinetic study was 0.323 ng/mL.

Biotransformation
Orally administered imiquimod is rapidly and extensively metabolised into two main metabolites.

Elimination
The small amount of medicinal product which was absorbed into the systemic circulation was promptly excreted by both urinary and faecal routes at a mean ratio of approximately 3 to 1.

The apparent half-life following topical dosing of 3.75% imiquimod cream in the pharmacokinetic study was calculated as approximately 29 hours.