Imikeraderm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMIQUIMODERM

Composition:

Active substance: imiquimod;

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

Excipients: isostearic acid, benzyl alcohol, white soft paraffin (stabilized with butylhydroxytoluene E 321), cetyl alcohol, stearyl alcohol, polysorbate 60, sorbitan monostearate type I, glycerol, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), xanthan gum, purified water.

Pharmaceutical form. Cream.

Main physicochemical characteristics: homogeneous cream, white to yellowish in color.

Pharmacotherapeutic group. Chemotherapeutic agents for topical use. Antiviral agents. ATC code D06B B10.

Pharmacological Properties

Pharmacodynamics

Imiquimod is an immune response modifier. Saturation binding studies suggest the presence of membrane receptors for imiquimod on relevant immune cells. Imiquimod does not have direct antiviral activity. In animal models, imiquimod is effective against viral infections and acts as an antitumor agent, primarily by inducing the production of alpha-interferon and other cytokines.

Increased systemic levels of alpha-interferon and other cytokines following topical application of imiquimod have been demonstrated in pharmacokinetic studies.

Clinical Efficacy

The efficacy of imiquimod applied three times per week for one or two 4-week treatment courses separated by a 4-week treatment-free period was evaluated in two double-blind, controlled clinical trials. Patients had clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic actinic keratosis lesions on the balding scalp or face within a contiguous treatment area of 25 cm². Treatment was administered to 4–8 actinic keratosis lesions. The complete clearance rate (imiquimod minus placebo) for the combined studies was 46.1% (95% CI: 39.0%–53.1%).

Data from two combined observational studies at one year indicate a recurrence rate of 27% (35/128 patients) among patients who achieved complete clinical response after one or two treatment courses. The recurrence rate per lesion was 5.6% (41/737). Corresponding recurrence rates in the placebo group were 47% (8/17 patients) and 7.5% (6/80 lesions).

Two open-label, randomized, controlled clinical trials compared the effects of imiquimod and topical diclofenac in the long-term treatment of patients with actinic keratosis, specifically assessing the risk of progression to in situ or invasive squamous cell carcinoma (SCC). Treatment was administered according to approved recommendations. If the treated actinic keratosis area did not completely clear, additional treatment cycles could be initiated. All patients were followed until study exit or up to 3 years after randomization. Results were obtained from a meta-analysis of both studies.

Overall, 482 patients were enrolled in these studies, of whom 481 received study treatment: 243 patients were treated with imiquimod and 238 with topical diclofenac. The actinic keratosis treatment area was located on the balding scalp or face with a contiguous area of approximately 40 cm². At baseline, the median number of clinically typical actinic keratosis lesions was 7 in both treatment groups. Clinical experience over the 3-year study period included 90 patients who received 3 or more imiquimod treatment courses and 80 patients who received 5 or more imiquimod treatment courses.

Regarding the primary histological progression endpoint, histological progression to in situ or invasive SCC occurred in 13 of 242 patients (5.4%) in the imiquimod group and in 26 of 237 patients (11.0%) in the diclofenac group over 3 years; the difference was -5.6% (95% CI: -10.7% to 0.7%). Specifically, histological progression to invasive SCC occurred in 4 of 242 patients (1.7%) in the imiquimod group and in 7 of 237 patients (3.0%) in the diclofenac group over the 3-year period.

Complete clinical clearance of the treated actinic keratosis area at week 20 (approximately 8 weeks after completion of the initial treatment cycle) was observed in 126 of 242 patients (52.1%) treated with imiquimod and in 84 of 237 patients (35.4%) treated with topical diclofenac; the difference was 16.6% (95% CI: 7.7%–25.1%). Recurrences of actinic keratosis lesions were assessed in patients who achieved complete clinical clearance of the treated area. In these studies, recurrence was defined as the presence of at least one actinic keratosis lesion on the previously cleared area, which could be either a lesion recurring at the same site as a previously cleared lesion or a new lesion appearing anywhere within the treated actinic keratosis area. The risk of lesion recurrence on the treated area (as defined above) by 12 months was 39.7% (50 of 126 patients) for patients treated with imiquimod compared to 50.0% (42 of 84 patients) for patients treated with topical diclofenac (difference: -10.3% [95% CI: -23.6% to 3.3%]); by 36 months, the recurrence risk was 66.7% (84 of 126 patients) for imiquimod-treated patients and 73.8% (62 of 84 patients) for diclofenac-treated patients (difference: -7.1% [95% CI: -19.0% to 5.7%]).

For patients experiencing recurrence of actinic keratosis lesions (as defined above) on a fully cleared area, the probability of achieving complete lesion clearance after an additional treatment course with imiquimod was 80%, compared to approximately 50% probability with a repeat course of topical diclofenac.

Paediatric Population

The approved indication, actinic keratosis, is not typically observed in children and therefore has not been studied. Imiquimod-containing cream was evaluated in four randomized, placebo-controlled, double-blind studies in children aged 2 to 15 years with molluscum contagiosum (imiquimod n = 576, placebo n = 313).

These studies failed to demonstrate efficacy of imiquimod in any of the treatment regimens evaluated (three times/week for ≤16 weeks and seven times/week for ≤8 weeks).

Pharmacokinetics

Following topical application in humans, less than 0.9% of a radiolabeled imiquimod dose is absorbed through the skin. The small amount of drug absorbed into the systemic circulation is rapidly excreted in urine and feces in a ratio of approximately 3:1. After single or multiple topical applications, the drug concentration in blood serum did not reach the quantification limit (>5 ng/mL).

Systemic exposure (transdermal penetration) was calculated based on recovery of carbon-14 [14C] from imiquimod in urine and feces.

Minimal systemic absorption of imiquimod from the 5% cream was observed in 58 patients with actinic keratosis treated three times weekly for 16 weeks. The extent of transdermal absorption did not change significantly between the first and last dose in this study. Maximum serum drug concentration (Cmax) at the end of week 16 was reached between 9 and 12 hours after application and was 0.1, 0.2, and 1.6 ng/mL following application to the face (12.5 mg, 1 single-use sachet), scalp (25 mg, 2 sachets), and hands (75 mg, 6 sachets), respectively. Application surface area was not controlled in the scalp and hand/arm groups. Dose proportionality was not observed. The apparent elimination half-life was approximately 10 times longer than the 2-hour half-life observed after subcutaneous administration in a previous study, suggesting prolonged retention of the drug in the skin. Urinary excretion in these patients was less than 0.6% of the applied dose at week 16.

Paediatric Population

Pharmacokinetic properties of imiquimod after single and multiple topical applications were studied in children with molluscum contagiosum (MC). Systemic exposure data indicated that the extent of imiquimod absorption following application to molluscum-contagiosum-affected skin in children aged 6–12 years was low and comparable to that in healthy adults and adults with molluscum contagiosum. In younger patients aged 2–5 years, absorption, based on Cmax values, was higher than in adults.

Clinical characteristics.

Indications.

The cream is used for topical treatment of:

• Actinic keratosis (AK) without signs of hypertrophy or hyperkeratosis, with typical clinical presentation, on the face or scalp in adult patients with normally functioning immune systems, when the size or number of lesions limits the effectiveness and/or appropriateness of cryotherapy, and when other topical treatment methods are contraindicated or less suitable.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted. This also applies to studies involving medicinal products that suppress the immune system. Interactions with systemically administered medicinal products are expected to be minimal due to the low skin absorption of imiquimod-based creams.

Given the immunostimulatory properties, the cream containing imiquimod should be used with caution in patients receiving medicinal products that suppress the immune system (see section "Special precautions for use").

Special precautions for use.

Avoid contact of the cream with eyes, lips, and nostrils.

Imiquimod may exacerbate inflammatory skin conditions.

The medicinal product should be used with caution in patients with autoimmune diseases (see section "Interaction with other medicinal products and other forms of interaction"). The benefit-risk balance of imiquimod treatment should be carefully considered in these patients due to the potential risk of exacerbation of autoimmune disease.

The medicinal product should be used with caution in patients after organ transplantation (see section "Interaction with other medicinal products and other forms of interaction"). The benefit-risk balance of imiquimod treatment should be carefully considered in these patients due to the potential risk of organ rejection or graft-versus-host reaction.

Treatment with imiquimod-containing cream is not recommended until the skin has healed following prior medical or surgical treatment.

Application to affected skin may increase systemic absorption of imiquimod, thereby increasing the risk of adverse reactions (see sections "Overdose" and "Undesirable effects").

The use of occlusive dressings during treatment with imiquimod-containing cream is not recommended.

In rare cases, strong local inflammatory reactions, including weeping or erosion, may occur, sometimes only after several applications of imiquimod-containing cream.

Local inflammatory reactions may be accompanied by, or even preceded by, systemic signs and symptoms resembling influenza, such as malaise, fever, nausea, myalgia, and chills. Discontinuation of the medicinal product should be considered.

Imiquimod should be used with caution in patients with impaired hematological reserve (see section "Undesirable effects").

If lesions appear clinically atypical for actinic keratosis or if there is suspicion of a malignant neoplasm, a biopsy should be performed to determine appropriate treatment.

The efficacy of imiquimod in treating actinic keratosis on eyelids, nostrils, ears, or on the vermilion border of the lips has not been evaluated.

There are very limited data on the use of imiquimod for treating actinic keratosis at anatomical sites other than the face or scalp. Available data on treatment of actinic keratosis in the axillary region or on the hands do not confirm efficacy; therefore, such treatment is not recommended.

Imiquimod is not recommended for the treatment of actinic lesions with marked hyperkeratosis or hypertrophy, as seen in cutaneous horn.

During treatment and until full recovery, the affected skin will likely appear significantly different from healthy skin. Local skin reactions are common, but their intensity usually decreases during treatment or resolves after discontinuation of imiquimod-containing cream. There is a correlation between the degree of complete clearance and the intensity of local skin reactions (e.g., erythema). These local skin reactions may be associated with stimulation of a local immune response. If necessary due to patient discomfort or intensity of local skin reactions, a treatment break of several days may be considered. Treatment with imiquimod-containing cream may be resumed once skin reactions have subsided.

No treatment course should exceed 4 weeks, including missed doses or rest periods.

The clinical outcome of treatment can be assessed approximately 4–8 weeks after completion of therapy, once the treated skin has recovered.

There is no clinical experience with the use of imiquimod-containing cream in immunocompromised patients.

Information regarding retreatment of actinic keratosis lesions that cleared after one or two treatment courses but subsequently recurred is provided in the sections "Pharmacodynamics" and "Posology and method of administration."

Open clinical trial data indicate that patients with more than eight actinic keratosis lesions show a lower rate of complete skin clearance compared to patients with fewer than eight lesions.

Areas of skin undergoing treatment should be protected from sunlight.

Imikeraderm contains methyl parahydroxybenzoate and propyl parahydroxybenzoate (E 218 and E 216), which may cause allergic reactions (possibly delayed).

Imikeraderm contains cetyl alcohol and stearyl alcohol, which may cause local skin reactions (e.g., contact dermatitis).

Imikeraderm contains benzyl alcohol, which may cause allergic reactions and mild local irritation.

Imikeraderm contains butylated hydroxytoluene (E 321), which may cause local skin reactions (e.g., contact dermatitis) or irritation of the eyes and mucous membranes.

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the use of imiquimod during pregnancy. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, fetal development, parturition, or postnatal development. Caution should be exercised when prescribing the medicinal product to pregnant women.

Breastfeeding

Since imiquimod is detected in blood serum after single and repeated topical applications at concentrations below the limit of quantification (> 5 ng/mL), there are no specific recommendations regarding the use of the medicinal product during breastfeeding.

Ability to affect the speed of reactions when driving vehicles or operating machinery.

The medicinal product Imikeraderm cream has no effect or negligible effect on the ability to drive vehicles or operate machinery.

Dosage and Administration

Dosage

Treatment should be initiated and supervised by a physician. The imiquimod-containing cream should be applied three times per week (for example, on Monday, Wednesday, and Friday) for 4 weeks, applied before bedtime and left on the skin for approximately 8 hours. A sufficient amount of cream should be applied to cover the entire treatment area. After a 4-week treatment period, a 4-week treatment-free period should follow, after which clearance of actinic keratosis lesions should be assessed. If any lesions persist, treatment should be repeated for another 4 weeks.

Maximum recommended dose: one sachet.

Consider discontinuing treatment if severe local inflammatory reactions occur (see section "Special precautions"), or if an infection develops at the treatment site. In the latter case, appropriate measures should be taken. Each treatment course should not exceed 4 weeks, including any dose omissions or treatment breaks.

If, approximately 8 weeks after the last 4-week treatment course, complete clearance of the treated area has not been achieved, an additional 4-week treatment course with ImikeraDerm may be considered.

Alternative therapy is recommended if the treated lesion(s) show an inadequate response to ImikeraDerm.

Lesions of actinic keratosis that cleared after one or two treatment courses and later recurred may be retreated with ImikeraDerm cream for one or two additional courses after a treatment break of at least 2 weeks (see section "Pharmacodynamics").

If a dose is missed, the patient should apply the cream as soon as remembered, and then continue treatment according to the usual schedule. However, the cream must not be applied more than once per day.

Administration

Before applying the imiquimod-containing cream, the patient should wash the treatment areas with mild soap and water and dry thoroughly. Apply a sufficient amount of cream to completely cover the entire treatment area. The cream should be gently rubbed into the treatment area until fully absorbed. The cream should be applied before bedtime and left on the skin for approximately 8 hours. During this time, the patient should avoid showering or bathing. After the 8-hour period, the cream should be washed off with warm water and mild soap. The medicinal product must not be reused from a previously opened sachet. Hands must be washed thoroughly with warm water and soap before and after applying the cream.

Children

Not recommended for children under 18 years of age. There are no data on the use of imiquimod in children and adolescents for the approved indications. ImikeraDerm should not be used in children for the treatment of molluscum contagiosum due to insufficient efficacy for this indication (see section "Pharmacodynamics").

Overdose

With topical application, systemic overdose of imiquimod-containing cream is unlikely due to minimal skin absorption. Animal studies in rabbits showed that the lethal dose with topical application exceeds 5 g/kg. Prolonged overdose with topical application of imiquimod-containing cream may cause severe local skin reactions.

Following accidental ingestion, symptoms such as nausea, vomiting, headache, myalgia, and fever may occur, but this would require a single intake of 200 mg of imiquimod, equivalent to the content of approximately 16 sachets. The most clinically significant adverse reaction observed after repeated oral doses of ≥ 200 mg was arterial hypotension, which resolved following oral and intravenous infusion therapy.

Adverse reactions.

a) General description:

In the pivotal studies evaluating the use of the medicinal product three times per week for up to 2 treatment courses of 4 weeks each, 56% of patients receiving imiquimod treatment reported at least one adverse reaction. The most frequently reported adverse reactions, considered probably or possibly related to the imiquimod-containing cream, were application site reactions (22% of patients receiving imiquimod treatment). Patients using imiquimod also reported certain systemic adverse reactions, including myalgia (2%).

Adverse reactions observed in a placebo-controlled, phase III clinical study in actinic keratosis involving 252 patients treated with imiquimod cream are listed below. These adverse reactions are considered to have at least a possible causal relationship with imiquimod treatment.

b) Tabulated list of adverse reactions:

Adverse reactions are classified by frequency as very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100). Information on adverse reactions occurring less frequently in clinical studies is not included.

c) Common adverse reactions:

In clinical studies of the cream containing imiquimod applied three times a week for 4 or 8 weeks, the most common local reactions were itching (14%) and burning sensation (5%). Severe erythema (24%) and severe crusting (20%) were very common. Local skin reactions such as erythema are likely to be an extension of the pharmacological effect of the cream containing imiquimod. See information on treatment-free periods in sections "Special instructions" and "Dosage and administration".

Skin infections have been observed during treatment with imiquimod. Although no serious consequences have been reported, the possibility of infection at the site of damaged skin should always be considered.

Cases of localized hypopigmentation and hyperpigmentation following application of the cream containing imiquimod have been reported. Follow-up data indicate that in some patients these skin color changes may be permanent.

In clinical studies of imiquimod for the treatment of actinic keratosis, the incidence of alopecia at and around the application site was 0.4% (5/1214).

In clinical studies, decreases in hemoglobin, white blood cell count, absolute neutrophil count, and platelet count were observed. Such decreases are not considered clinically significant in patients with normal hematological reserve. Patients with impaired hematological reserve were not included in clinical studies. During the post-marketing period, cases of hematological parameter reductions requiring clinical intervention have been reported. Elevations in liver enzymes have also been reported during the post-marketing period.

Rare reports of exacerbation of autoimmune diseases have been received.

During clinical studies, rare cases of dermatological reactions to the drug at distant skin sites, including erythema multiforme, were reported. Serious skin reactions reported during the post-marketing period include erythema multiforme, Stevens-Johnson syndrome, and cutaneous lupus erythematosus.

d) Children:

Imiquimod has been studied in controlled clinical trials involving children (see sections "Pharmacodynamics" and "Dosage and administration"). There was no evidence of systemic reactions. Local reactions at the site of imiquimod application occurred more frequently than with placebo; however, the frequency and intensity of these reactions were similar to those observed in approved indications for adult treatment. There is no evidence of serious adverse reactions caused by imiquimod in children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at https://aisf.dec.gov.ua.

Shelf life. 36 months.

Storage conditions.

Store at a temperature not exceeding 25°C. Keep out of the reach of children. Do not reuse opened sachets.

Packaging.

250 mg of cream in a sachet. 12 or 24 sachets per pack.

Prescription status. Prescription only.

Manufacturer: mibe GmbH & Co. KG.

Manufacturer's address and location of operations:

Muenchenstrasse 15, Brehna, Saxony-Anhalt, 06796, Germany.