Zyclara

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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. 
 



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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. 



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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).  
 
 



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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  



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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 



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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. 
 



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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. 
 
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. 
 
 



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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. 



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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 
 
 
 



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

 
 
 



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ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY  
AND USE  

 
     C. OTHER CONDITIONS AND REQUIREMENTS OF THE  
 MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO  
 THE SAFE AND EFFECTIVE USE OF THE MEDICINAL  
 PRODUCT 
 

 
 



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A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Swiss Caps GmbH 
Grassingerstraße 9 
83043 Bad Aibling 
Germany  
 
3M Health Care Limited 
Derby Road 
Loughborough 
Leicester 
LE11 5SF 
United Kingdom. 
 
MEDA Pharma GmbH & Co. KG 
Benzstraße 1 
61352 Bad Homburg 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medicinal prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zyclara 3.75% cream  
imiquimod 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 9.375 mg of imiquimod in 250 mg cream (3.75%). 
Each gram of cream contains 37.5 mg of imiquimod. 
 
 
3. LIST OF EXCIPIENTS 
 
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. 
 
Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Cream 
14 sachets  
28 sachets  
56 sachets  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Cutaneous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
For single use only. Discard any cream remaining in a sachet after use. 
 
 
 
 



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8. EXPIRY DATE 
 
Exp 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Meda AB 
Box 906 
170 09 Solna 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/783/001 14 sachets 
EU/1/12/783/002 28 sachets 
EU/1/12/783/003 56 sachets 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Zyclara 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
 



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18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



19 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
 
SACHET TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Zyclara 3.75% cream  
Imiquimod 
Cutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
Exp 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
250 mg  
 
 
6. OTHER 
 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 



21 

Package leaflet: Information for the user 
 

Zyclara 3.75% cream 
Imiquimod 

 
Read all of this leaflet carefully before you start using this medicine because it contains  
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their sign of illness are the same as yours. 
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 

1.   What Zyclara is and what it is used for 
2.   What you need to know before you use Zyclara 
3.   How to use Zyclara 
4.   Possible side effects 
5.   How to store Zyclara  
6.   Content of the pack and other information 

 
 
1. What Zyclara is and what it is used for 
 
Zyclara 3.75% cream contains the active substance imiquimod, which is an Immune Response 
Modifier (to stimulate the human immune system). 
 
This medicine is prescribed for the treatment of actinic keratosis in adults. 
 
This medicine stimulates your body’s own immune system to produce natural substances which help 
fight your actinic keratosis.  
 
Actinic keratosis appears as rough areas of skin found in people who have been exposed to a lot of 
sunshine over the course of their lifetime. These areas can be the same colour as your skin or are 
greyish, pink, red or brown. They can be flat and scaly, or raised, rough, hard and warty. 
 
This medicine should only be used for actinic keratosis on the face or scalp if your doctor has decided 
that it is the most appropriate treatment for you. 
 
 
2. What you need to know before you use Zyclara 
 
Do not use Zyclara.  
 
- if you are allergic to imiquimod or any of the other ingredients of this medicine (listed in 

section 6). 
 

Warnings and precautions 
 
Talk to your doctor or pharmacist before using Zyclara: 

• if you have previously used this medicine or other similar preparations in a different 
concentration.  

• if you have problems with your immune system or if you take medicine to suppress your 
immune system (e.g. after an organ transplant). 



22 

• if you have an abnormal blood count. 
 
 

General instructions during treatment 
 

• If you have recently had surgery or medicinal treatment, wait until the area to be treated has 
healed before using this medicine. 

• Avoid contact with the eyes, lips and nostrils. In the event of accidental contact, remove 
cream by rinsing with water. 

• Only use the cream externally (on the skin of face or scalp). 
• Do not use more cream than your doctor has advised. 
• Do not cover the treated area with bandages or other dressings after you have applied this 

medicine. 
• If the treated site becomes too uncomfortable, wash the cream off with mild soap and water. 

Once the discomfort stops you can resume your treatment schedule as recommended. The 
cream should not be applied more than once daily. 

• Do not use sunlamps or tanning-beds, and avoid exposure to sunlight as much as possible 
during treatment with this medicine. If you go outside during the day use sunscreen and wear 
protective clothing and a wide-brimmed hat. 

 
Local skin reactions 
 
While using Zyclara, you may experience local skin reactions because of the way it acts on your skin. 
These reactions can be a sign that the medicine is working as intended. 
 
Whilst using Zyclara and until healed, the treatment area is likely to appear noticeably different from 
normal skin. There is also a possibility that existing inflammation may temporarily worsen. 
This medicine may also cause flu-like symptoms (including tiredness, nausea, fever, muscle and joint 
pain, and shivering) before or during the occurrence of local skin reactions.  
If flu-like symptoms or feeling discomfort or intense local skin reactions occur, a rest period of 
several days may be taken. You could resume treatment with imiquimod cream after the skin reaction 
has moderated. However, neither 2-week treatment cycle should be extended due to missed doses or 
rest periods.  
The intensity of the local skin reactions tend to be lower in the second cycle than in the first treatment 
cycle with Zyclara. 
 
Response to treatment cannot be adequately assessed until resolution of local skin reactions. You 
should continue treatment as prescribed. 
This medicine may reveal and treat actinic keratosis that have not be seen or felt before, and these 
may later go away. You should continue application for the full treatment course even if all actinic 
keratosis appear to be gone. 
 
Children and adolescents 
 
This medicine should not be given to children below the age of 18 years because the safety and 
efficacy in patients below the age of 18 years have not been established. There are no data available 
of the use of imiquimod in children and adolescents. 
 
Other medicines and Zyclara 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
If you receive immunosuppressive medicinal products which inhibit the immune system, tell your 
doctor before starting the treatment. 



23 

Avoid the concomitant use of Zyclara and any other imiquimod cream in the same treatment area. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before using this medicine.  
 
Your doctor will discuss the risks and benefits of using Zyclara during pregnancy. Studies in animals 
do not indicate direct or indirect harmful effects in pregnancy.  
 
It is not known whether imiquimod passes into breast milk. You should not use Zyclara if you are 
breast-feeding or plan to breast-feed. Your doctor will discuss if you should discontinue breast-
feeding or discontinue Zyclara treatment. 
 
Driving and using machines 
 
This medicine has no or negligible influence on the ability to drive and use machines. 
 
Zyclara contains methyl parahydroxybenzoate, propyl parahydroxybenzoate, cetyl alcohol, 
stearyl alcohol and benzyl alcohol 
 
Methyl parahydroxybenzoate (E 218), and propyl parahydroxybenzoate (E 216), may cause allergic 
reactions (possibly delayed). Cetyl alcohol and stearyl alcohol may cause local skin reactions (e.g. 
contact dermatitis).  
This medicine contains 5 mg benzyl alcohol in each sachet. Benzyl alcohol may cause allergic 
reactions and mild local irritation. 
 
 
3. How to use Zyclara  
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. Do not use this medicine until your doctor has shown you the right way to use it. 
 
This medicine should only be used for actinic keratosis on the face and scalp. 
 
Dosage 
Apply this medicine to the affected area once a day just before bedtime. 
Maximum daily dose is 2 sachets (500 mg = 2 sachets of 250 mg each). 
This medicine should not be applied to areas larger than either the full face or balding scalp.  
 
Method of administration 
 

 

1. Before going to bed, wash your hands and the 
treatment area carefully with mild soap and water. Dry hands 
thoroughly and allow the area to dry. 
 

 

2.  Open a new sachet of Zyclara just before use and 
squeeze some cream onto your fingertip. No more than 2 
sachets should be used per application. 
 



24 

 

3. Apply a thin layer of Zyclara to the affected area. Rub 
gently into the area until the cream vanishes. Avoid contact 
with the eyes, lips and nostrils. 
 

 

4. After application of the cream, throw away the opened 
sachet. Wash hands well with soap and water. 
 

 

5. Leave Zyclara on the skin for about 8 hours. Do not 
shower or bathe the area during this time. Do not cover the 
treated area with bandages or other dressings. 
 

 

6. After about 8 hours, wash the area where Zyclara was 
applied with mild soap and water. 
 

 
 
Duration of treatment 
The treatment starts with a daily application for two weeks, followed by a break without any 
application for two weeks, and then ends with a daily application again for two weeks. 
 
If you use more Zyclara than you should 
 
If you have applied too much cream, wash the extra away with mild soap and water. 
When any skin reaction has gone you may then continue with your treatment in the recommended 
regular schedule. The cream should not be applied more than once daily. 
 
If you accidentally swallow this medicine please contact your doctor immediately. 
 
If you forget to use Zyclara 
 
If you miss a dose of Zyclara, wait until the next night to apply it and then continue with the regular 
schedule. The cream should not be applied more than once daily. Each treatment cycle should last no 
longer than two weeks, even if you have missed doses. 
 
If you stop using Zyclara 
 
Talk to your doctor before you stop treatment with Zyclara. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Seek medical attention right away if any of these severe side effects occur when using this medicine: 



25 

Serious skin reactions (frequency not known) with skin lesions or spots on your skin that start out as 
small red areas and progress to look like mini targets, possibly with symptoms such as itching, fever, 
overall ill feeling, achy joints, vision problems, burning, painful or itchy eyes and mouth sores. If you 
experience these, stop using this medicine and tell your doctor immediately. 
 
In some individuals a lowering of blood counts was noted (frequency not known). This might make 
you more susceptible to infections, make you bruise more easily or cause tiredness. If you notice any 
of these symptoms, tell your doctor. 
 
If there is pus or another sign of skin infection (frequency not known), discuss this with your doctor. 
 
Many of the side effects of this medicine are due to its local action on your skin. Local skin reactions 
can be a sign that the medicine is working as intended. If your skin reacts badly or becomes too 
uncomfortable when using this medicine, stop applying the cream and wash the area with mild soap 
and water. Then contact your doctor or pharmacist. He may advise you to stop applying this medicine 
for a few days (i.e. to have a short rest from treatment).  
 
The following side effects with imiquimod were reported: 
 
Very common (may affect more than 1 in 10 people) 
- Skin redness, scabbing, skin scaling, discharge, skin dryness, skin swelling, skin ulcer, and 

reduced skin pigmentation at the application site 
 
Common (may affect up to 1 in 10 people) 
- Further reactions at the application site e.g. skin inflammation, itching, pain, burning, irritation, 

and rash 
- Swollen glands 
- Headache 
- Dizziness 
- Loss of appetite 
- Nausea 
- Diarrhoea 
- Vomiting 
- Flu-like symptoms 
- Fever 
- Pain 
- Muscle and joint pain 
- Chest pain 
- Insomnia 
- Tiredness 
- Viral infection (herpes simplex) 
- Increase in blood glucose 
 
Uncommon (may affect up to 1 in 100 people) 
- Changes at the application site, e.g. bleeding, small swollen areas in the skin, inflammation, pins 

and needles, increased sensitivity to touch, scarring, feeling of warmth, skin breakdown, blisters 
or pustules 

- Weakness 
- Shivering 
- Lack of energy (lethargy) 
- Discomfort 
- Swelling of the face 
- Back pain 
- Pain in limbs 
- Stuffy nose 



26 

- Throat pain 
- Eye irritation 
- Swelling of the eyelid 
- Depression 
- Irritability 
- Dry mouth 
- Abdominal pain 
 
Rare (may affect up to 1 in 1,000 people) 
- Flaring up of autoimmune conditions (a disease that results from an abnormal immune response is 

an autoimmune disease) 
- Skin reactions remote from the application site 
 
Frequency not known (frequency cannot be estimated from the available data)  
- Changes in skin colour 

Some patients have experienced changes in skin colour in the area where Zyclara was applied. 
While these changes have tended to improve with time, in some patients they may be permanent. 

- Hair loss 
A small number of patients have experienced hair loss at the treatment site or surrounding area. 

- Increase in liver enzymes 
There have been reports of increased liver enzymes. 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Zyclara 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and the label after 
EXP. 
The expiry date refers to the last day of that month. 
Do not store above 25 °C. 
 
Sachets should not be re-used once opened. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
6. Contents of the pack and other information 
 
What Zyclara contains 
- The active substance is imiquimod. Each sachet contains 9.375 mg of imiquimod in 250 mg 

cream (100 mg of cream contains 3.75 mg imiquimod). 
- The other ingredients are 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 (see also section 2 “Zyclara 
contains methyl parahydroxybenzoate, propyl parahydroxybenzoate, cetyl alcohol, stearyl 
alcohol and benzyl alcohol”). 

 



27 

What Zyclara looks like and contents of the pack 
- Each Zyclara 3.75% cream sachet contains 250 mg of a white to slightly yellow cream with a 

uniform appearance. 
- Each box contains 14, 28 or 56 single-use polyester/ white low density polyethylene/aluminium 

foil sachets. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Meda AB 
Pipers väg 2A 
170 73 Solna 
Sweden 
 
Manufacturer  
 
Swiss Caps GmbH 
Grassingerstraße 9 
83043 Bad Aibling 
Germany 
       
3M Health Care Limited  
Derby Road  
Loughborough 
Leicestershire   
LE11 5SF, United Kingdom 
 
MEDA Pharma GmbH & Co. KG 
Benzstraße 1 
61352 Bad Homburg 
Germany 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Mylan EPD bvba/sprl 
Terhulpsesteenweg, 6A 
B-1560 Hoeilaart 
Tél/Tel: +32 2 658 61 00 
 

Luxembourg/Luxemburg 
Mylan EPD bvba/sprl  
Terhulpsesteenweg, 6A 
B-1560 Hoeilaart 
Tél/Tel: +32 2 658 61 00 
 

България 
Майлан ЕООД 
бул. Ситняково 48, ет. 7 
Офис сграда „Сердика Офиси“ 
1505 София 
Тел: +359 2 44 55 400 
 

Magyarország 
Mylan EPD Kft. 
1138 Budapest 
Váci út 150 
Tel: +36 1 465 2100 
 

Česká republika 
MEDA Pharma s.r.o. 
Evropská 2590/33C 
Prague 6 160 00 
Tel: +420 222 004 400 
 

Malta 
V.J. Salomone Pharma Limited  
Upper Cross Road 
Marsa, MRS 1542 
Tel: +356 21 22 01 74 
 



28 

Danmark 
Mylan Denmark ApS 
Borupvang 1 
2750 Ballerup 
Tlf: +45 28 11 69 32 
 
 

Nederland 
Mylan Healthcare B.V. 
Krijgsman 20 
1186 DM Amstelveen 
Tel: +31 (0)20 426 3300 
 

Deutschland 
MEDA Pharma GmbH & Co. KG 
Benzstraße 1 
61352 Bad Homburg 
Tel: +49 (0) 6172 888 01 
 

Norge 
Mylan Healthcare Norge AS  
Hagaløkkveien 26 
1383 Asker 
Tlf: +47 66 75 33 00 
 

Eesti 
Meda Pharma SIA 
Liivalaia 13/15  
11018 Tallinn 
Tel: +372 62 61 025 
 

Österreich 
MEDA Pharma GmbH 
Guglgasse 15 
1110 Wien 
Tel: + 43 (0)1 86 390 0 
 

Ελλάδα 
MEDA Pharmaceuticals A.E. 
Αγίου Δημητρίου 63 
17456 Άλιμος  
Τηλ: +30 210 6 77 5690 
 

Polska 
Mylan Healthcare Sp. z o.o. 
ul. Postępu 21B 
02-676 Warszawa 
Tel: +48 22 546 6400 
 

España 
Mylan Pharmaceuticals, S.L. 
C/ Plom, 2-4, 5ª planta 
08038 - Barcelona 
Tel: +34 900 102 712 
 

Portugal 
BGP Products, Unipessoal, Lda. 
Av. D. João II,  
Edifício Atlantis, nº 44C – 7.3 e 7.4 
1990-095 Lisboa 
Tel: +351 214 127 200 
 

France 
Mylan Medical SAS 
40-44 rue Washington 
75008 Paris 
Tél: +33 (0)1 56 64 10 70 
 

România 
BGP PRODUCTS SRL 
Reprezentanța Romania 
Calea Floreasca nr. 169A 
Floreasca Business Park  
014459 București 
Tel.: +40 372 579 000 
 

Hrvatska 
Mylan Hrvatska d.o.o. 
Koranska 2 
10 000  Zagreb 
Tel: +385 1 235 059 90  

Slovenija 
Mylan Healthcare d.o.o. 
Dolenjska cesta 242c 
1000 Ljubljana 
Tel: +386 1 23 63 180 
 

Ireland 
Mylan Ireland Limited 
Newenham Court 
Northern Cross, Malahide Road 
Dublin 17 
Tel: +353 (0) 87 1694982 
 

Slovenská republika 
MEDA Pharma spol. s r.o. 
Trnavská cesta 50 
821 02 Bratislava 
Tel: +421 2 32 199 100 
 



29 

Ísland 
Icepharma hf 
Lyngháls 13 
110 Reykjavík 
Sími: +354 540 8000 
 

Suomi/Finland 
Meda Oy 
Vaisalantie 4/Vaisalavägen 4 
02130 Espoo/Esbo 
Puh/Tel: +358 20 720 9550 
 

Italia 
Meda Pharma S.p.A. 
Via Felice Casati, 20 
20124 Milano 
Tel: +39 039 73901 
 

Sverige 
Meda AB 
Box 906 
170 09 Solna 
Tel: +46 (0)8 630 1900 
 

Κύπρος 
Βαρνάβας Χατζηπαναγής Λτδ 
Λεωφ. Γιάννου Κρανιδιώτη 226 
ΤK 2234, Λατσιά, Λευκωσία 
Τηλ.: +357 22207700 
 

United Kingdom 
Mylan Products Ltd. 
Station Close  
Potters Bar  
Hertfordshire  
EN6 1TL 
Tel: +44 1707 853000 

Latvija 
Meda Pharma SIA 
101 Mūkusalas str. 
Rīga LV‐ 1004 
Tālr: +371 67616137 
 

 

Lietuva 
Meda Pharma SIA 
Žalgirio str. 90-100 
Vilnius LT-09303  
Tel. + 370 52059367 
 

 

 
This leaflet was last revised in (MM/YYYY). 

 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET