This information is intended for use by health professionals

1. Name of the medicinal product

Zyclara 3.75% cream

2. Qualitative and quantitative composition

Each sachet contains 9.375 mg of imiquimod in 250 mg cream (3.75%).

Each gram of cream contains 37.5 mg of imiquimod.

Excipients with known effects:

Methyl parahydroxybenzoate (E 218) 2.0 mg/g cream

Propyl parahydroxybenzoate (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.

3. Pharmaceutical form

Cream.

White to faintly yellow cream with a uniform appearance.

4. Clinical particulars
4.1 Therapeutic indications

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.

4.2 Posology and method of administration

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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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).

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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
5.1 Pharmacodynamic 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.

Two open-label randomized, controlled studies investigated the long-term effects of imiquimod 5% (and not with this 3.75% product) in comparison to topical diclofenac (3% gel). In these studies, the treated AK field was located on the balding scalp or face with a contiguous area of about 40 cm2 and presenting with a median number of 7 clinically typical AK lesions at baseline. Study treatments were given as officially recommended. These studies showed that imiquimod was better than topical diclofenac in preventing the histological progression of AK lesions to in-situ or invasive squamous cell carcinoma (SCC). In addition, these studies supported the use of up to two additional treatment cycles of imiquimod when the AK lesions are not completely cleared or if the AK lesions recurred after successful initial treatment with imiquimod.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Zyclara in all subsets of the paediatric population in actinic keratosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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

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

A 18-month mouse carcinogenicity study by dermal administration on three days a week did not induce tumours at the application site. Only in female mice, the incidences of hepatocellular adenomas were slightly greater than those for controls. The incidence corresponds well with the spectrum of spontaneous tumours, as is known in mice in correspondence with their age. Therefore, these findings are considered to be incidental. As imiquimod has low systemic absorption from human skin, and is not mutagenic, any risk to humans from systemic exposure is likely to be low. Furthermore, tumours were not seen at any site in a 2-year oral carcinogenicity study in rats.

Imiquimod cream was evaluated in a photocarcinogenicity bioassay in albino hairless mice exposed to simulated solar ultraviolet radiation (UVR). Animals were administered imiquimod cream three times per week and were irradiated 5 days per week for 40 weeks. Mice were maintained for an additional 12 weeks. Tumours occurred earlier and in greater number in the group of mice administered the vehicle cream in comparison with the low UVR control group. The significance for man is unknown. Topical administration of imiquimod cream resulted in no tumour enhancement at any dose, in comparison with the vehicle cream group.

6. Pharmaceutical particulars
6.1 List of excipients

Isostearic acid

Benzyl alcohol

Cetyl alcohol

Stearyl alcohol

White soft paraffin

Polysorbate 60

Sorbitan stearate

Glycerol

Methyl parahydroxybenzoate (E 218)

Propyl parahydroxybenzoate (E 216)

Xanthan gum

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

6.4 Special precautions for storage

Do not store above 25 °C.

Sachets should not be re-used once opened.

6.5 Nature and contents of container

Boxes of 14, 28, and 56 single-use polyester/ white low density polyethylene/ aluminium foil sachets, containing 250 mg of cream.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Meda AB

Pipers väg 2A

170 73 Solna

Sweden

8. Marketing authorisation number(s)

EU/1/12/783/001-003

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 23/08/2012

Date of latest renewal: 22/03/2017

10. Date of revision of the text

02/2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europe.eu.