This information is intended for use by health professionals

1. Name of the medicinal product

Bascellex 50 mg/g cream

2. Qualitative and quantitative composition

Each sachet contains 12.5 mg of imiquimod in 250 mg cream (5 %). 1 g of cream contains 50 mg of imiquimod.

Excipients with known effects

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 50.0 mg/g cream

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Cream.

White to slightly yellow smooth cream.

4. Clinical particulars
4.1 Therapeutic indications

Imiquimod cream is indicated for the topical treatment of

- 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.

Please also refer to section 5.1.

4.2 Posology and method of administration

Posology

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 imiquimod treatment may be considered.

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

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 imiquimod cream following an at least 12 weeks treatment pause (see section 5.1).

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 indication.

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

Method of administration

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.

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

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).

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).

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.

Healthcare professionals should be aware that if this product comes into contact with dressings, clothing and bedding, the fabric can be easily ignited with a naked flame. Patients should be warned of this risk and advised to keep away from fire when using this product.

This medicine contains 12.5 mg benzyl alcohol in each sachet which is equivalent to 50 mg/g. Benzyl alcohol may cause mild local irritation.

4.5 Interaction with other medicinal products and other forms of interaction

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).

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/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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

a) General description

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) Tabulated list of adverse reactions

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.

Infections and infestations

Infection

Uncommon

Pustules

Uncommon

Rhinitis

Uncommon

Influenza

Uncommon

Blood and lymphatic system disorders

Lymphadenopathy

Uncommon

Metabolism and nutrition disorders

Anorexia

Common

Psychiatric disorders:

Depression

Uncommon

Nervous system disorders

Headache

Common

Eye disorders

Conjunctival irritation

Uncommon

Eyelid oedema

Uncommon

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Uncommon

Pharyngo laryngeal pain

Uncommon

Gastrointestinal disorders

Nausea

Common

Diarrhoea

Uncommon

Skin and subcutaneous tissue disorders

Actinic keratosis

Uncommon

Erythema

Uncommon

Face oedema

Uncommon

Skin ulcer

Uncommon

Musculoskeletal and connective tissue disorders

Myalgia

Common

Arthralgia

Common

Pain in extremity

Uncommon

General disorders and administration site conditions

Application site pruritus

Very common

Application site pain

Common

Application site burning

Common

Application site irritation

Common

Application site erythema

Common

Application site reaction

Common

Application site bleeding

Uncommon

Application site papules

Uncommon

Application site paraesthesia

Uncommon

Fatigue

Common

Pyrexia

Uncommon

Asthenia

Uncommon

Rigors

Uncommon

Application site dermatitis

Uncommon

Application site discharge

Uncommon

Application site hyperaesthesia

Uncommon

Application site oedema

Uncommon

Application site scabbing

Uncommon

Application site scar

Uncommon

Application site swelling

Uncommon

Application site ulcer

Uncommon

Application site vesicles

Uncommon

Application site warmth

Uncommon

Discomfort

Uncommon

Inflammation

Uncommon

c) Frequently occurring adverse events

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.

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.

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.

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.

d) 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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
5.1 Pharmacodynamic 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.

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

Actinic keratosis (data available for the test product, Bascellex 50 mg/g cream)

Clinical efficacy

A randomized, double-blind, multiple-site, placebo-controlled, parallel-design, clinical study was performed to evaluate the therapeutic equivalence of the test product, Bascellex 50 mg/g to the reference product, imiquimod 5% cream in patients with actinic keratosis. Patients were randomized and treated for 8 weeks (two 4-week courses).

Efficacy evaluations were based on lesion counts, performed by Investigator at all clinic visits. The primary statistical analysis of interest was the proportion of patients considered to be a Complete Cure, defined as 100% clearance of all AK lesions within the treatment area.

For therapeutic equivalence evaluation of the primary endpoint in the PP and the mITT populations, the following results were observed: The 95% confidence interval for the difference between the proportion of patients considered a Complete Cure in the Test and the Reference product groups was contained within the equivalence interval of -20% to +20% for both populations. For the superiority analyses of the primary endpoint, the following results were observed: The proportion of patients considered Complete Cure in the Test and Reference groups was significantly higher at the 5% significance level (p < 0.05) than the proportion of patients considered Complete Cure in the Placebo group.

Therefore, both equivalence and superiority were demonstrated for the primary endpoint.

Actinic keratosis (data available for the reference product, imiquimod 5% cream)

Clinical efficacy

The efficacy of imiquimod applied 3 times per week for one or two courses of 4 weeks, separated by a 4 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 the balding scalp or face within a contiguous 25 cm2 treatment area. 4-8 AK lesions were treated. The complete 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 for vehicle were 47% (8/17 patients) and 7.5% (6/80 lesions).

Two open-label, randomised, controlled clinical trials compared the long-term effects of imiquimod with those of topical diclofenac in patients with actinic keratosis with respect to the risk of progression to in situ or invasive squamous cell carcinoma (SCC). Treatments were given as officially recommended. If the treated AK field was not completely cleared of lesions, additional treatment cycles could be started. All patients were followed-up until withdrawal or up to 3 years after randomisation. 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. The treated AK field was located on the balding scalp or face with a contiguous area of about 40 cm² for both 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, 80 patients 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 the imiquimod group and 26 of 237 patients (11.0%) of the diclofenac group were found to have a histological 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%) of the diclofenac group were found to have a histological progression to invasive SCC within the 3-year period.

A total of 126 of 242 patients treated with imiquimod (52.1%) and 84 of 237 patients treated with topical 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% to 25.1%). For those patients with complete clinical clearance of the treated AK field recurrence of AK lesions was evaluated. A patient was counted as recurrent in these trials if at least one AK lesion was observed in the completely cleared field whereby a recurrent lesion could be a lesion which occurred at 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% (50 of 126 patients) until month 12 for patients treated with imiquimod compared with 50.0% (42 of 84 patients) 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) for topical 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 of about 80% to become completely cleared again following an additional imiquimod treatment cycle compared with a chance of about 50% for a re-treatment with topical diclofenac.

Paediatric population

The approved indication actinic keratosis is a condition not generally seen within the paediatric population and was not studied.

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

The benefit-risk of the Bascellex 50 mg/g cream in the indications external genital and perianal warts and small superficial basal cell carcinomas, approved for the reference product imiquimod 5% cream, is unknown due to lack of data.

5.2 Pharmacokinetic properties

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 12.5 mg/250 mg 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

The pharmacokinetic properties of imiquimod following single and multiple topical application in paediatric patients with molluscum contagiosum (MC) have been investigated. The systemic exposure data demonstrated that the extent of absorption of imiquimod following topical application to the MC lesional skin of the paediatric patients aged 6-12 years was low and comparable to that observed in healthy adults and adults with actinic keratosis. In younger patients aged 2-5 years absorption, based on Cmax values, was higher compared to adults.

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 two-year mouse carcinogenicity study by dermal administration on three days a week did not induce tumours at the application site. However, the incidences of hepatocellular tumours among treated animals were greater than those for controls. The mechanism for this is not known, but 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 for a total of 52 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

Paraffin white soft

Polysorbate 60

Sorbitan monostearate

Glycerol

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Xanthan gum

Water, purified

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

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 12 or 24 single-use 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

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing authorisation number(s)

PL 31750/0134

9. Date of first authorisation/renewal of the authorisation

16/04/2018

10. Date of revision of the text

16/04/2018