CNL8

Dosage Form: nail lacquer
CNL8 (ciclopirox topical solution 8%)Nail Lacquer

CNL8 Description

CNL8 (ciclopirox topical solution, 8%) nail lacquer.

For use on fingernails and toenails and immediately adjacent skin only.

Not for use in eyes.

CNL8 (ciclopirox topical solution, 8%) nail lacquer contains a synthetic antifungal agent, ciclopirox. It is intended for topical use on fingernails and toenails and immediately adjacent skin.

Each gram of CNL8 (ciclopirox topical solution, 8%) nail lacquer contains 80 mg ciclopirox in a solution base consisting of ethyl acetate, NF; isopropyl alcohol, USP; and butyl monoester of poly[methylvinyl ether/maleic acid] in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.

CNL8 (ciclopirox topical solution, 8%) nail lacquer is a clear, colorless to slightly yellowish solution.

The chemical name for ciclopirox is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, with the molecular formula C12H17NO2 and a molecular weight of 207.27. The CAS Registry Number is 29342-05-0. The chemical structure is:

CNL8 - Clinical Pharmacology

Microbiology Mechanism of Action: The mechanism of action of ciclopirox has been investigated using various in vitro and in vivo infection models. One in vitro study suggested that ciclopirox acts by chelation of polyvalent cations (Fe+3 or Al+3) resulting in the inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell. The clinical significance of this observation is not known.


Activity in vitro and ex vivo:  In vitro methodologies employing various broth or solid media with and without additional nutrients have been utilized to determine ciclopirox minimum inhibitory concentration (MIC) values for the dermatophytic molds.(1-2) As a consequence, a broad range of MIC values, 1-20 mcg/mL were obtained for Trichophyton rubrum and Trichophyton mentagrophytes species. Correlation between in vitro MIC results and clinical outcome has yet to be established for ciclopirox.


One ex vivo study was conducted evaluating 8% ciclopirox against new and established Trichophyton rubrum and Trichophyton mentagrophytes infections in ovine hoof material.(3) After 10 days of treatment the growth of T. rubrum and T. mentagrophytes in the established infection model was very minimally affected. Elimination of the molds from hoof material was not achieved in either the new or established for infection models.


Susceptibility testing for Trichophyton rubrum species: In vitro susceptibility testing methods for determining ciclopirox MIC values against the dermatophytic molds, including Trichophyton rubrum species, have not been standardized or validated. Ciclopirox MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of Trichophyton rubrum are susceptible or resistant to ciclopirox have not been established.


Resistance Studies: have not been conducted to evaluate drug resistance development in T. rubrum species exposed to 8% ciclopirox topical solution. Studies assessing crossresistance to ciclopirox and other known antifungal agents have not been performed.


Antifungal Drug Interaction: No studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis is not recommended

PHARMACOKINETICS

As demonstrated in pharmacokinetic studies in animals and man, ciclopirox olamine is rapidly absorbed after oral administration and completely eliminated in all species via feces and urine. Most of the compound is excreted either unchanged or as glucuronide. After oral administration of 10 mg of radiolabeled drug (14Cciclopirox) to healthy volunteers, approximately 96% of the radioactivity was excreted renally within 12 hours of administration. Ninety four percent of the renally excreted radioactivity was in the form of glucuronides. Thus, glucuronidation is the main metabolic pathway of this compound.

Systemic absorption of ciclopirox was determined in 5 patients with dermatophytic onychomycoses, after application of CNL8 (ciclopirox topical solution, 8%) nail lacquer to all 20 digits and adjacent 5 mm of skin once daily for six months.  Random serum concentrations and 24 hour urinary excretion of ciclopirox were determined at two weeks and at 1,2, 4 and 6 months after initiation of treatment and 4 weeks post-treatment.  In this study, ciclopirox serum levels ranged from 12-80 ng/mL. Based on urinary data, mean absorption of ciclopirox from the dosage form was less than 5% of the applied dose. One month after cessation of treatment, serum and urine levels of ciclopirox were below the limit of detection.


In two vehicle-controlled trials, patients applied CNL8 (ciclopirox topical solution, 8%) nail lacquer to all toenails and affected fingernails. Out of a total of 66 randomly selected patients on active treatment, 24 had detectable serum ciclopirox concentrations at some point during the dosing interval (range 10.0-24.6 ng/mL). It should be noted that eleven of these 24 patients took concomitant medication containing ciclopirox as ciclopirox olamine (Loprox® Cream, 0.77%).


The penetration of the CNL8 (ciclopirox topical solution, 8%) nail lacquer was evaluated in an in vitro investigation. Radiolabeled ciclopirox applied once to onychomycotic toenails that were avulsed demonstrated penetration up to a depth of approximately 0.4 mm. As expected, nail plate concentrations decreased as a function of nail depth. The clinical significance of these findings in nail plates is unknown. Nail bed concentrations were not determined.

INDICATIONS & USAGE

(To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.)

CNL8 (ciclopirox topical solution,8%) nail lacquer as a component of a comprehensive management program, is indicated as topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Tricho-phyto rubrum. The comprehensive management program includes removal of the unattached, infected nails as frequently as monthly, by a health care professional who has special competence in the diagnosis and treatment of nail disorders, including minor nail procedures.

No studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis, is not recommended.


CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used only under medical supervision as described above. 


The effectiveness and safety of CNL8 (ciclopirox topical solution, 8%) nail lacquer in the following populations have not been studied. The clinical trials with use of CNL8 (ciclopirox topical solution, 8%) nail lacquer excluded patients who: were pregnant or nursing, planned to become pregnant, had a history of immunosuppression (e.g., extensive, persistent, or unusual distribution of derma-tomycoses, extensive seborrheic dermatitis, recent or recurring herpes zoster, or persistent herpes simplex), were HIV seropositive, received organ transplant, required medication to control epilepsy, were insulin dependent diabetics or had diabetic neuropathy. Patients with severe plantar (moccasin) tinea pedis were also excluded.


The safety and efficacy of using CNL8 (ciclopirox topical solution, 8%) nail lacquer daily for greater than 48 weeks have not been established.

Clinical Studies

The results of use of CNL8 (ciclopirox topical solution, 8%) nail lacquer in treatment of onychomycosis of the toenail without lunula involvement were obtained from two double-blind, placebo-controlled studies conducted in the US. In these studies, patients with onychomycosis of the great toenails without lunula involvement were treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer in conjunction with monthly removal of the unattached, infected toenail by the investigator.  CNL8 (ciclopirox topical solution, 8%) nail lacquer was applied for 48 weeks. At baseline, patients had 20-65% involvement of the target great toenail plate. Statistical significance was demonstrated in one of two studies for the endpoint “complete cure” (clear nail and negative mycology), and in two studies for the endpoint “almost clear” (10% nail involvement and negative mycology) at the end of study. These results are presented below.

At Week 48 (plus Last Observation Carried Forward for the Intent-to-Treat (ITT) Population


                                                            Study 312                                Study 313

                                                            Active              Vehicle             Active                 Vehicle

Complete Cure*                                     6/110 (5.5%)     1/109 (0.9%)     10/118 (8.5%)      0/117 (0%)

Almost Clear**                                      7/107 (6.5%)      1/108 (0.9%)     14/116 (12%)       1/115 (0%)

Negative Mycology Alone ***                  30/105 (29%)     12/106 (11%)    41/115 (36%)       10/114 (9%)

*Clear nail and negative Mycology

** Less than or equal to 10% nail involvement and negative mycology



The summary of reported patient outcomes for the ITT population at 12 weeks following the end of treatment are presented below. Note that post-treatment efficacy assessments were scheduled only for patients who achieved a complete cure.


Post-treatment Week 12 Data for Patients Who Achieved Complete Cure at Week 48


                                                                                    Study 312                             Study 313

                                                                                    Active         Vehicle               Active             Vehicle

Number of Treated Patients                                            112             111                     119                 118

Completed Cure at Week 48                                           6                 1                         10                  1


Post-treatment Week 12 Outcomes:

   Patients Missing all Week 12 Assessments                  2                 0                         2                     0

   Patients with Week 12 Assessments                            4                 1                         8                     0

       Complete Cure                                                        3                 1                         4                     0

       Almost Clear                                                           2*                1                         1*                    0

       Negative Mycology                                                  3                 1                          5                    0

* Four patients (from studies 312 and 313) who were completely cured did not have post-treatment Week 12 planimetry data.

Contraindications

CNL8 (ciclopirox topical solution, 8%) nail lacquer is contraindicated in individuals who have shown hypersensitivity to any of its components.

Warnings

CNL8 (ciclopirox topical solution, 8%) nail lacquer is not for ophthalmic, oral, or intravaginal use. For use on nails and immediately adjacent skin only.

Precautions

If a reaction suggesting sensitivity or chemical irritation should occur with the use of CNL8 (ciclopirox topical solution, 8%) nail lacquer treatment should be discontinued and appropriate therapy instituted. So far there is no relevant clinical experience with patients with insulin dependent diabetes or who have diabetic neuropathy. The risk of removal of the unattached, infected nail, by the health care professional and trimming by the patient should be carefully considered before prescribing to patients with a history of insulin dependent diabetes mellitus or diabetic neuropathy.

INFORMATION FOR PATIENTS

Patients should have detailed instruction regarding the use of CNL8 (ciclopirox topical solution, 8%) nail lacquer as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product.

The patient should be told to:

1. Use CNL8 (ciclopirox topical solution, 8%) nail lacquer as directed by a health care professional. Avoid contact witheyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. CNL8 (ciclopirox topical solution, 8%) nail lacquer is for external use only.


2.CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis). Contact with the surrounding skin may produce mild, transient irritation (redness).


3.  Removal of the unattached,infected nail, as frequently as monthly, by a health care professional is needed with the use of this medication. Inform a health care professional if you have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate nail management program.


4.  Inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing).


5.  Up to 48 weeks of daily applications with CNL8 (ciclopirox topical solution, 8%) nail lacquer and professional removal of the unattached,infected nail, as frequently as monthly, are considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement).


6.  Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.


7.  A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a completely clear or almost clear toenail.


8.  Do not use the medication for any disorder other than that for which it is prescribed. Do not use nail polish or other nail cosmetic products on the treated nails.


9. Avoid use near heat or open flame, because product is flammable.

CARCINOGENESIS, MUTAGENESIS and IMPAIRMENT OF FERTILITY

No carcinogenicity study was conducted with CNL8 (ciclopirox topical solution, 8%) nail lacquer formulation. A carcinogenicity study of ciclopirox (1% and 5% solutions in polyethylene glycol 400) in female mice dosed topically twice per week for 50 weeks followed by a 6-month drug-free observation period prior to necropsy revealed no evidence of tumors at the application sites.

In human systemic tolerability studies following daily application (~340 mg of CNL8 (ciclopirox topical solution, 8%) nail lacquer) in subjects with distal subungual onychomycosis, the average maximal serum level of ciclopirox was 31±28 ng/mL after two months of once daily applications. This level was 159 times lower than the lowest toxic dose and 115 times lower than the highest nontoxic dose in rats and dogs fed 7.7 and 23.1 mg ciclopirox (as ciclopirox olamine)/kg/day.

The following in vitro genotoxicity tests have been conducted with ciclopirox: evaluation of gene mutation in Ames Salmonella and E. coli assays (negative); chromosome aberration assays in V79 Chinese hamster lung fibroblasts, with and without metabolic activation (positive); gene mutation assay in HGPRT-test with V79 Chinese hamster lung fibroblasts (negative); unscheduled DNA synthesis in human A549 cells (negative); and BALB/c3T3 cell transformation assay (negative). In an in vivo Chinese hamster bone marrow cytogenetic assay, ciclopirox was negative for chromosome aberrations at 5,000 mg/kg.

Oral reproduction studies in rats at doses up to 3.85 mg ciclopirox (as ciclopirox olamine)/kg/day [equivalent to approximately 1.4 times the potential exposure at the maximum recommended human topical dose (MRHTD)] did not reveal any specific effects on fertility or other reproductive parameters. MRHTD (mg/m2) is based on the assumption of 100% systemic absorption of 27.12 mg ciclopirox (~340 mg CNL8 (ciclopirox topical solution, 8%) nail lacquer that will cover all the fingernails and toenails including 5 mm proximal and lateral fold area plus onycholysis to a maximal extent of 50%.

PREGNANCY

Teratogenic effects: Pregnancy Category B Teratology studies in mice, rats, rabbits, and monkeys at oral doses of up to 77, 23, 23, or 38.5 mg, respectively, of ciclopirox as ciclopirox olamine/kg/day (14, 8, 17, and 28 times MRHTD), or in rats and rabbits receiving topical doses of up to 92.4 and 77 mg/kg/day, respectively (33 and 55 times MRHTD), did not indicate any significant fetal malformations. There are no adequate or well controlled studies of topically applied ciclopirox in pregnant women. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NURSING MONTHERS

It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when CNL8

(ciclopirox topical solution, 8%) nail lacquer is administered to a nursing woman.

PEDIATRIC USE

Based on the safety profile in adults, CNL8 (ciclopirox topical solution, 8%) nail lacquer is considered safe for use in children twelve years and older. No clinical trials have been conducted in the pediatric population.

GERIATRIC USE

Based on the safety profile in adults, CNL8 (ciclopirox topical solution, 8%) nail lacquer is considered safe for use in children twelve years and older. No clinical trials have been conducted in the pediatric population.

ADVERSE REATIONS

In the vehicle-controlled clinical trials conducted in the US, 9% (30/327) of patients treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer and 7% (23/328) of patients treated with vehicle reported treatment- emergent adverse events (TEAE) considered by the investigator to be causally related to the test material. The incidence of these adverse events, within each body system, was similar between the treatment groups except for Skin and Appendages: 8% (27/327) and 4% (14/328) of subjects in the ciclopirox and vehicle groups reported at least one adverse event, respectively. The most common were rash-related adverse

events: periungual erythema and erythema of the proximal nail fold were reported more frequently in patients treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer (5% [16/327]) than in patients treated with vehicle (1% [3/328]). Other TEAEs thought to be causally related included nail disorders such as shape change, irritation, ingrown toenail, and discoloration.

The incidence of nail disorders was similar between the treatment groups (2% [6/327] in the CNL8 (ciclopirox topical solution, 8%) nail lacquer group and 2% [7/328] in the vehicle group). Moreover, application site reactions and/or burning of the skin occurred in 1% of patients in 1% of patients treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer (3/327) and vehicle (4/328).  A 21-Day Cumulative Irritancy study was conducted under conditions of semi-occlusion.  Mild reactions were seen in 46% of patients with CNL8 (ciclopirox topical solution, 8%) nail lacquer 32% with the vehicle and 2% with the negative control, but all were reactions of mild transient erythema.  There was no evidence of allergic contact sensitization for either the CNL8 (ciclopirox topical solution, 8%) nail lacquer or the vehicle base. In a separate study of the photosensitization potential of CNL8 (ciclopirox topical solution, 8%) nail lacquer in a maximized test design that included the occluded application of sodium lauryl sulfate, no photoallergic reactions were noted. In

four subjects localized allergic contact reactions were observed.  In the vehicle-controlled studies, one patient treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer discontinued treatment due to a rash, localized to the palm (causal relation to test material undetermined).


Use of CNL8 (ciclopirox topical solution, 8%) nail lacquer for 48 additional weeks was evaluated in an open-label extension study conducted in patients previously treated in the  vehicle-controlled studies. Threecpercent (9/281) of subjects treated with CNL8 (ciclopirox topical solution, 8%) nail lacquer experienced at least one TEAE that the investigator thought was causally related to the test material. Mild rash in the form of periungual erythema (1% [2/281]) and nail disorders (1% [4/281]) were the most frequently reported. Four patients discontinued because of TEAEs. Two of the four had events considered to be related to test material: one patient’s great toenail “broke away” and another had an elevated creatine phosphokinase level on Day 1 (after 48 weeks of treatment with vehicle in the previous vehicle-controlled study).


To report SUSPECTED ADVERSE REACTIONS contact JSJ Pharmaceuticals at 800-499-4468.

DOSAGE and ADMINISTRATION

CNL8 (ciclopirox topical solution, 8%) nail lacquer should be used as a component of a comprehensive management program for onychomycosis.  Removal of the unattached, infected nail, as frequently as monthly, by a health care professional, weekly trimming by the patient, and daily application of the medication are all integral parts of this therapy. Careful consideration of the appropriate nail management program should be given to patients with diabetes (see PRECAUTIONS).


Nail Care By Health Care Professionals:  Removal of the unattached, infected nail, as frequently as monthly, trimming of onycholytic nail, and filing of excess horny material should be performed by professionals trained in treatment of nail disorders.


Nail Care By Patient:  Patients should file away (with emery board) loose nail material and trim nails, as required, or as directed by the health care professional, every seven days after CNL8 (ciclopirox topical solution, 8%) nail lacquer is removed with alcohol. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied once daily (preferably at bedtime or eight hours before washing) to all affected nails with the applicator brush provided. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied evenly over the entire nail plate.


If possible, CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis).


CNL8 (ciclopirox topical solution, 8%) nail lacquer should not be removed on a daily basis. Daily applications should be made over the previous coat and removed with alcohol every seven days. This cycle should be repeated throughout the duration of therapy.

How is CNL8 Supplied

CNL8 nail kit (ciclopirox topical solution, 8%), Swabplus nail lacquer remover, emery board – which contains 3 - 5 ml bottles of CNL8 (ciclopirox topical solution, 8%) nail lacquer (glass bottles with screw caps which are fitted with brushes), 25 - 0.15 ml nail lacquer remover swabs and 1 emery board (NDC 68712-027-01).

CNL8 (ciclopirox topical solution, 8%) nail lacquer, single count 5 ml bottle (NDC 68712-027-03).

Protect from light (e.g., store the bottle in the carton after every use).

CNL8 (ciclopirox topical solution, 8%) nail lacquer should be stored at room temperature between 59° and 86° F (15° and 30° C).

INFORMATION FOR PATIENTS

Patients should have detailed instruction regarding the use of CNL8 (ciclopirox topical solution, 8%) nail lacquer as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product.


The patient should be told to:


1. Use CNL8 (ciclopirox topical solution, 8%) nail lacquer as directed by a health care professional.  Avoid contact with eyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. CNL8 (ciclopirox topical solution, 8%) nail lacquer is for external use only.


2. CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, CNL8 (ciclopirox topical solution, 8%) nail lacquer should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis). Contact with the surrounding skin may produce mild, transient irritation (redness).


3. Removal of the unattached, infected nail, as frequently as monthly, by a health care professional is needed with the use of this medication. Inform a health care professional if you have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate nail management program.


4.  Inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing).


5.  Up to 48 weeks of daily applications with CNL8 (ciclopirox topical solution, 8%) nail lacquer and professional removal of the unattached, infected nail, as frequently as monthly, are considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement).


6.  Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.


7.  A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a completely clear or almost clear toenail.


8.  Do not use the medication for any disorder other than that for which it is prescribed.


9.  Do not use nail polish or other nail cosmetic productson the treated nails.


10. Avoid use near heat or open flame, because product is flammable.


Manufactured for:


Innocutis Holdings LLC

Charleston, SC 29401

1-800-499-4468

CNL8nails.com

REFERENCES

References:


1. Dittmar W., Lohaus G. 1973. HOE296, A new antimycotic compound with a broad antimicrobial spectrum. Arzneim- Forsch./Drug Res. 23:670-674.


2. Niewerth et al., 1998. Antimicrobial susceptibility testing of dermatophytes: Comparison of the agar macrodilution and broth micro dilution tests. Chemotherapy. 44:31-35.


3. Yang et al., 1997. A new simulation model for studying in vitro topical penetration of antifungaldrugs into hard keratin.  J. Mycol. Med. 7:195-98.  Gantrez is a registered trademark of GAF Corporation


Rev. 419:00 12/07

CNL8   ciclopirox   solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68712-027 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CICLOPIROX (CICLOPIROX) CICLOPIROX 2.28 g  in 1 mL

Inactive Ingredients Ingredient Name Strength ETHYL ACETATE   ISOPROPYL ALCOHOL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 68712-027-01 3 BOTTLE In 1 CARTON contains a BOTTLE, GLASS (68712-027-03) 1 68712-027-03 5 mL In 1 BOTTLE, GLASS This package is contained within the CARTON (68712-027-01) 2 68712-027-03 5 mL In 1 BOTTLE, GLASS None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078270	10/31/2008

Labeler - Innocutis Holdings LLC (071501252)

Revised: 12/2011Innocutis Holdings LLC

sinecatechins Topical application

sin-e-KAT-e-kins

Commonly used brand name(s)

In the U.S.

• Veregen

Available Dosage Forms:

• Ointment

Therapeutic Class: Keratolytic

Uses For sinecatechins

Sinecatechins is used to treat external warts around the genital and rectal areas called condylomata acuminata. It is not used to treat warts that occur inside the vagina, penis, or rectum .

sinecatechins is available only with your doctor's prescription .

Before Using sinecatechins

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For sinecatechins, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to sinecatechins or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of sinecatechins in the pediatric population. Safety and efficacy have not been established .

Geriatric

Insufficient information is available on the relationship of age to the effects of sinecatechins in geriatric patients. It may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of sinecatechins. Make sure you tell your doctor if you have any other medical problems, especially:

• Inflamed, irritated, or infected skin—Use with caution. sinecatechins may make this condition worse .

• Weakened immune system—It is not known if sinecatechins is safe to use with this condition .

Proper Use of sinecatechins

Use the medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it longer than directed .

Wash your hands with soap and water before and after using sinecatechins .

sinecatechins is for use on the skin only. Do not get it inside your eyes, nose, mouth, vagina, or anus. Do not use on open wounds or on skin areas that have cuts or scrapes. If it does get on these areas, rinse it off right away .

Do not use sinecatechins on moles, birthmarks, or any other warts until you discuss it with your doctor .

Women using tampons should insert the tampon first before applying the ointment. If the tampon needs to be changed while the ointment is on the skin, avoid getting the ointment into the vagina .

Men who are not circumcised and treating genital warts under the foreskin should draw back the foreskin and clean the area daily .

Do not wash off the ointment from the treated area before you apply the next dose. When you wash the treatment area or bathe, apply the ointment afterwards .

Do not cover the treated area with a bandage unless your doctor has told you to. You may wear loose-fitting underwear after applying sinecatechins .

Keep using sinecatechins until all the warts have cleared up. However, you should not use sinecatechins for longer than 16 weeks .

Dosing

The dose of sinecatechins will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of sinecatechins. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For topical dosage form (ointment):
  
  • For warts on the genital or rectal areas:
    
    • Adults—Apply a thin layer (about an 0.5 cm strand) to the affected area three times a day. Rub it in gently.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  

Missed Dose

If you miss a dose of sinecatechins, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store in the refrigerator. Do not freeze.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using sinecatechins

sinecatechins may make your skin more sensitive to sunlight. Do not expose the area being treated with sinecatechins to sunlight, sunlamps, or tanning beds .

Avoid having genital, oral, or anal sex while the medicine is on your skin. Make sure you wash the ointment off your skin before you engage in any sexual activity. Also, the medicine contains oils that can weaken latex (rubber) condoms, or diaphragms causing them not to work properly .

Sinecatechins will not keep you from spreading genital warts to other people. Talk with your doctor about safe sex practices .

sinecatechins is not a cure for genital or anal warts. You may still develop new warts during or after your treatment .

sinecatechins may stain your clothes and bedding .

Do not use cosmetics or any other skin care products on the same skin area on which you use sinecatechins, unless directed otherwise by your doctor .

If your condition does not improve within 16 weeks, or if it becomes worse, check with your doctor .

Many patients experience redness, swelling, sores or blisters, burning, or itching after using sinecatechins. If you experience a severe skin reaction, remove the ointment by washing the area with mild soap and water and contact your doctor right away .

sinecatechins Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Blistering, peeling, or loosening of the skin


• breakdown of skin


• burning of skin


• cracking of skin


• flushing, redness of skin


• hardening or thickening of skin


• irritation of skin


• itching skin


• pain or discomfort in skin


• swelling of skin


• unusually warm skin

Less common

• Bleeding of skin


• blood in urine


• break in the skin, especially associated with blue-black discoloration, swelling, or drainage of fluid


• burning or itching around anus


• changes in skin coloring


• discharge from skin


• dryness of skin


• increased frequency of urination


• increased sensitivity to pain


• increased sensitivity to touch


• pain or burning during urination


• peeling of one area of skin


• pelvic pain


• problems with foreskin of penis


• rash with flat lesions or small raised lesions on the skin


• scarring of skin


• skin rash, encrusted, scaly and oozing


• skin rash on the face


• swollen, painful, or tender lymph glands in neck, armpit, or groin


• tingling in the hands and feet

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: sinecatechins Topical application side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More sinecatechins Topical application resources

• Sinecatechins Topical application Side Effects (in more detail)
• Sinecatechins Topical application Use in Pregnancy & Breastfeeding
• Sinecatechins Topical application Support Group
• 0 Reviews for Sinecatechins Topical application - Add your own review/rating

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• Condylomata Acuminata

Victoza 6 mg / ml solution for injection in pre-filled pen

1. Name Of The Medicinal Product

Victoza

2. Qualitative And Quantitative Composition

One ml of solution contains 6 mg of liraglutide*. One pre-filled pen contains 18 mg liraglutide in 3 ml.

* human glucagon-like peptide-1 (GLP-1) analogue produced by recombinant DNA technology in Saccharomyces cerevisiae.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection in pre-filled pen (injection).

Clear, colourless, isotonic solution; pH=8.15.

4. Clinical Particulars

4.1 Therapeutic Indications

Victoza is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control:

In combination with:

– Metformin or a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin or sulphonylurea.

In combination with:

– Metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with insufficient glycaemic control despite dual therapy.

4.2 Posology And Method Of Administration

Posology

To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least one week, the dose should be increased to 1.2 mg. Some patients are expected to benefit from an increase in dose from 1.2 mg to 1.8 mg and based on clinical response, after at least one week the dose can be increased to 1.8 mg to further improve glycaemic control. Daily doses higher than 1.8 mg are not recommended.

Victoza can be added to existing metformin or to a combination of metformin and thiazolidinedione therapy. The current dose of metformin and thiazolidinedione can be continued unchanged.

Victoza can be added to existing sulphonylurea or to a combination of metformin and sulphonylurea therapy. When Victoza is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4).

Self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza. However, when initiating treatment with Victoza in combination with a sulphonylurea, blood glucose self-monitoring may become necessary to adjust the dose of the sulphonylurea.

Special populations

Elderly (>65 years old): No dose adjustment is required based on age. Therapeutic experience in patients

Renal impairment: No dose adjustment is required for patients with mild renal impairment (creatinine clearance 60-90 ml/min). There is very limited therapeutic experience in patients with moderate renal impairment (creatinine clearance of 30-59 ml/min) and no therapeutic experience in patients with severe renal impairment (creatinine clearance below 30 ml/min). Victoza can currently not be recommended for use in patients with moderate and severe renal impairment including patients with end-stage renal disease (see section 5.2).

Hepatic impairment: The therapeutic experience in patients with all degrees of hepatic impairment is currently too limited to recommend the use in patients with mild, moderate or severe hepatic impairment (see section 5.2).

Paediatric population: Victoza is not recommended for use in children below 18 years of age due to lack of data on its safety and efficacy.

Method of administration

Victoza should not be administered intravenously or intramuscularly.

Victoza is administered once daily at any time, independent of meals, and can be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site and timing can be changed without dose adjustment. However, it is preferable that Victoza is injected around the same time of the day, when the most convenient time of the day has been chosen. For further instructions on administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Victoza is not a substitute for insulin.

The addition of liraglutide in patients already treated with insulin has not been evaluated and is therefore not recommended.

There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I-II. There is no experience in patients with congestive heart failure NYHA class III-IV.

There is limited experience in patients with inflammatory bowel disease and diabetic gastroparesis and Victoza is therefore not recommended in these patients. The use of Victoza is associated with transient gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea.

Use of GLP-1 analogues has been associated with the risk of pancreatitis. There have been few reported events of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Victoza and other potentially suspect medicinal products should be discontinued.

Thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials in particular in patients with pre-existing thyroid disease (see section 4.8).

Patients receiving Victoza in combination with a sulphonylurea may have an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by a reduction in the dose of sulphonylurea.

Signs and symptoms of dehydration, including altered renal function have been reported in patients treated with Victoza. Patients treated with Victoza should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions with other active substances related to cytochrome P450 and plasma protein binding.

The small delay of gastric emptying with liraglutide may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption. Few patients treated with liraglutide reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicinal products.

Paracetamol

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1000 mg. Paracetamol C_max was decreased by 31% and median t_max was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required.

Atorvastatin

Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin C_max was decreased by 38% and median t_max was delayed from 1 h to 3 h with liraglutide.

Griseofulvin

Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin C_max increased by 37% while median t_max did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.

Digoxin

A Single dose administration of digoxin 1 mg with liraglutide resultated in a reduction of digoxin AUC by 16%; C_max decreased by 31%. Digoxin median t_max was delayed from 1 h to 1.5 h. No adjustment of digoxin dose is required based on these results.

Lisinopril

A single dose administration of lisinopril 20 mg with liraglutide resultated in a reduction of lisinopril AUC by 15% ; C_max decreased by 27%. Lisinopril median t_max was delayed from 6 h to 8 h with liraglutide. No dose adjustment of lisinopril is required based on these results.

Oral contraceptives

Liraglutide lowered ethinyloestradiol and levonorgestrel C_max by 12 and 13%, respectively, following administration of a single dose of an oral contraceptive product. T_max was delayed by 1.5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinyloestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with liraglutide.

Warfarin and other coumarin derivatives

No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of liraglutide treatment in patients on warfarin or other coumarin derivatives more frequent monitoring of INR (International Normalised Ratio) is recommended.

Insulin

No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and insulin detemir when administering a single dose of insulin detemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Victoza in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Victoza should not be used during pregnancy, and the use of insulin is recommended instead. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Victoza should be discontinued.

Lactation

It is not known whether liraglutide is excreted in human milk. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk is low. Non-clinical studies have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section 5.3). Because of lack of experience, Victoza should not be used during breast-feeding.

Fertility

Apart from a slight decrease in the number of live implants, animal studies did not indicate harmful effects with respect to fertility.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Victoza is used in combination with a sulphonylurea.

4.8 Undesirable Effects

In five large long-term clinical trials over 2500 patients have received treatment with Victoza alone or in combination with metformin, a sulphonylurea (with or without metformin) or metformin plus rosiglitazone.

Frequencies are defined as: Very common (

The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders: nausea and diarrhoea were very common, whereas vomiting, constipation, abdominal pain, and dyspepsia were common. At the beginning of Victoza therapy, these gastrointestinal adverse reactions may occur more frequently. These reactions usually diminish within a few days or weeks on continued treatment. Headache and nasopharyngitis were also common. Furthermore, hypoglycaemia was common, and very common when Victoza is used in combination with a sulphonylurea. Major hypoglycaemia has primarily been observed when combined with a sulphonylurea.

Table 1 lists related adverse reactions identified from Phase III combination-studies with Victoza. The table presents adverse reactions that occurred with a frequency >5% if the frequency was higher among Victoza-treated patients than patients treated with comparator. The table also includes adverse reactions with a frequency

Table 1 Adverse reactions identified from long-term controlled phase III studies

Adverse reaction	Frequency of adverse reaction by treatment group
	Liraglutide with metformin	Liraglutide with glimepiride	Liraglutide with metformin and glimepiride	Liraglutide with metformin and rosiglitazone
Infections and infestations
Nasopharyngitis		Common		Common
Bronchitis			Common
Metabolism and nutrition disorders
Hypoglycaemia		Common	Very common	Common
Anorexia	Common	Common	Common	Common
Appetite decreased	Common			Common
Nervous system disorders
Headache	Very common		Common	Common
Dizziness	Common
Gastrointestinal disorders
Nausea	Very common	Common	Very common	Very common
Diarrhoea	Very common	Common	Very common	Very common
Vomiting	Common	Common	Common	Very common
Dyspepsia	Common	Common	Common	Common
Abdominal pain upper			Common
Constipation		Common	Common	Common
Gastritis	Common
Flatulence				Common
Abdominal distension				Common
Gastroesophageal reflux disease				Common
Abdominal discomfort		Common
Toothache			Common
Gastroenteritis viral				Common
General disorders and administration site conditions
Fatigue				Common
Pyrexia				Common

In a clinical trial with Victoza as monotherapy rates of hypoglycaemia reported with Victoza were lower than rates reported for patients treated with active comparator (glimepiride). The most frequently reported adverse events were gastrointestinal and infections and infestations.

Hypoglycaemia

Most episodes of confirmed hypoglycaemia in clinical studies were minor. No episodes of major hypoglycaemia were observed in the study with Victoza used as monotherapy. Major hypoglycaemia may occur uncommonly and has primarily been observed when Victoza is combined with a sulphonylurea (0.02 events/subject year). Very few episodes (0.001 events/subject year) were observed with administration of Victoza in combination with oral antidiabetics other than sulphonylureas.

Gastrointestinal adverse reactions

When combining Victoza with metformin, 20.7% of patients reported at least one episode of nausea, and 12.6% of patients reported at least one episode of diarrhoea. When combining Victoza with a sulphonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% of patients reported at least one episode of diarrhoea. Most episodes were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea.

Patients >70 years may experience more gastrointestinal effects when treated with liraglutide.

Patients with mild renal impairment (creatinine clearance 60-90 ml/min) may experience more gastrointestinal effects when treated with liraglutide.

Withdrawal

The incidence of withdrawal due to adverse reactions was 7.8% for Victoza-treated patients and 3.4% for comparator-treated patients in the long-term controlled trials (26 weeks or longer). The most frequent adverse reactions leading to withdrawal for Victoza-treated patients were nausea (2.8% of patients) and vomiting (1.5%).

Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-liraglutide antibodies following treatment with Victoza. On average, 8.6% of patients developed antibodies. Antibody formation has not been associated with reduced efficacy of Victoza.

Few cases (0.05%) of angioedema have been reported during all long-term clinical trials with Victoza.

Injection site reactions

Injection site reaction has been reported in approximately 2% of subjects receiving Victoza in long-term (26 weeks or longer) controlled trials. These reactions have usually been mild and did not lead to discontinuation of Victoza.

Pancreatitis

Few cases (<0.2%) of acute pancreatitis have been reported during long-term clinical trials with Victoza.

Thyroid events

The overall rates of thyroid adverse events in all intermediate and long-term trials are 33.5, 30.0 and 21.7 events per 1000 subject years of exposure for total liraglutide, placebo and total comparators; 5.4, 2.1 and 1.2 events, respectively concern serious thyroid adverse events.

Thyroid neoplasms, increased blood calcitonin and goiters were the most frequently thyroid adverse events. The rates per 1,000 subject years of exposure were 6.8, 10.9 and 5.4 of liraglutide treated patients in comparison with 6.4, 10.7 and 2.1 of placebo treated and 2.4, 6.0 and 1.8 of total comparator treated patients respectively.

4.9 Overdose

In a clinical study of Victoza, one patient with type 2 diabetes experienced a single overdose of 17.4 mg subcutaneous (10 times the maximal recommended maintenance dose of 1.8 mg). Effects of the overdose included severe nausea and vomiting, but not hypoglycaemia. The patient recovered without complications.

In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other blood glucose lowering drugs, excl. insulins. ATC code: A10BX07

Mechanism of action

Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.

Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake.

Pharmacodynamic effects

Liraglutide has 24-hour duration of action and improves glycaemic control by lowering fasting and postprandial blood glucose in patients with type 2 diabetes mellitus.

Clinical efficacy

Five double-blind, randomised, controlled clinical trials were conducted to evaluate the effects of Victoza on glycaemic control. Treatment with Victoza produced clinically and statistically significant improvements in glycosylated haemoglobin A_1c (HbA_1c), fasting plasma glucose and post-prandial glucose compared with placebo.

These studies included 3,978 exposed patients with type 2 diabetes (2,501 subjects treated with Victoza), 53.7% men and 46.3% women, 797 subjects (508 treated with Victoza) were

There was an additional open-label randomised controlled study comparing liraglutide with exenatide.

In a 52 week clinical trial, the addition of insulin detemir to Victoza 1.8 mg and metformin in patients not achieving glycemic targets on Victoza and metformin alone, resulted in a HbA_1c decrease from baseline of 0.54%, compared to 0.20% in the Victoza 1.8 mg and metformin control group. Weight loss was sustained. There was a small increase in the rate of minor hypoglycaemic episodes (0.23 versus 0.03 events per subject years). The addition of liraglutide in patients already treated with insulin has not been evaluated (see section 4.4).

Glycaemic control

Victoza in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant (p<0.0001) and sustained reductions in HbA_1c compared with patients receiving placebo (Tables 2 and 3).

Table 2 Results of two 26 week trials. Victoza in combination with metformin and Victoza in combination with glimepiride.

Metformin add-on therapy	1.8 mg liraglutide + metformin3	1.2 mg liraglutide + metformin3	placebo + metformin3	Glimepiride2 + metformin3
N	242	240	121	242
Mean HbA1c (%) Baseline Change from baseline	8.4 -1.00	8.3 -0.97	8.4 0.09	8.4 -0.98
Patients (%) achieving HbA1c <7% All patients Previous OAD monotherapy	42.4 66.3	35.3 52.8	10.8 22.5	36.3 56.0
Mean body weight (kg) Baseline Change from baseline	88.0 -2.79	88.5 -2.58	91.0 -1.51	89.0 0.95
Glimepiride add-on therapy	1.8 mg liraglutide + glimepiride2	1.2 mg liraglutide + glimepiride2	Placebo + glimepiride2	rosiglitazone1 + glimepiride2
N	234	228	114	231
Mean HbA1c (%) Baseline Change from baseline	8.5 -1.13	8.5 -1.08	8.4 0.23	8.4 -0.44
Patients (%) achieving HbA1c <7% All patients Previous OAD monotherapy	41.6 55.9	34.5 57.4	7.5 11.8	21.9 36.1
Mean body weight (kg) Baseline Change from baseline	83.0 -0.23	80.0 0.32	81.9 -0.10	80.6 2.11

¹ Rosiglitazone 4 mg/day; ² glimepiride 4 mg/day; ³ metformin 2000 mg/day

Table 3 Results of two 26 week trials. Victoza in combination with metformin + rosiglitazone and Victoza in combination with glimepiride + metformin.

Metformin + rosiglitazone add-on therapy	1.8 mg liraglutide + metformin2 + rosiglitazone3	1.2mg liraglutide + metformin2 + rosiglitazone3	placebo + metformin2 + rosiglitazone3	N/A
N	178	177	175
Mean HbA1c (%) Baseline Change from baseline	8.56 -1.48	8.48 -1.48	8.42 -0.54
Patients (%) achieving HbA1c <7% All patients	53.7	57.5	28.1
Mean body weight (kg) Baseline Change from baseline	94.9 -2.02	95.3 -1.02	98.5 0.60
Metformin + glimepiride add-on therapy	1.8 mg liraglutide + metformin2+ glimepiride4	N/A	Placebo + metformin2+ glimepiride4	insulin glargine 1 + metformin2+ glimepiride4
N	230		114	232
Mean HbA1c (%) Baseline Change from baseline	8.3 -1.33		8.3 -0.24	8.1 -1.09
Patients (%) achieving HbA1c <7% All patients	53.1		15.3	45.8
Mean body weight (kg) Baseline Change from baseline	85.8 -1.81		85.4 -0.42	85.2 1.62

¹ The dosing of insulin glargine was open-labelled and was applied according to the following titration guideline. Titration of the insulin glargine dose was managed by the patient after instruction by the investigator.

Guideline for titration of insulin glargine

Self-measured FPG	Increase in insulin glargine dose (IU)
	No adjustment
>5.5 and <6.7 mmol/l (>100 and <120 mg/dl)	0 – 2 IUa