CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate carcinogenic potential have not been conducted with polidocanol. Polidocanol was negative in bacterial reverse mutation assays in Salmonella and E. coli, and in micronucleus assay conducted in mice. Polidocanol induced numerical chromosomal aberrations in cultured newborn Chinese hamster lung fibroblasts in the absence of metabolic activation.Polidocanol did not affect reproductive performance (fertility) of rats when administered intermittently at dosages up to 10 mg/kg (approximately equal to the maximum human dose on the basis of body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action The active ingredient of Asclera is polidocanol.Polidocanol is sclerosing agent that locally damages the endothelium of blood vessels. When injected intravenously, polidocanol induces endothelial damage. Platelets then aggregate at the site of damage and attach to the venous wall. Eventually, dense network of platelets, cellular debris, and fibrin occludes the vessel. Finally, the occluded vein is replaced with connective fibrous tissue.. 12.2 Pharmacodynamics. Polidocanol has concentration- and volume-dependent damaging effect on the endothelium of blood vessels.. 12.3 Pharmacokinetics. During the major effectiveness study (EASI-trial), scheduled blood samples were taken from sub-group of 22 patients to measure plasma levels of polidocanol after Asclera treatment of spider and reticular veins. Low systemic blood levels of polidocanol were seen in some patients.The mean t1/2 of polidocanol in patients with evaluable data receiving 4.5 -18.0 mg was 1.5 h.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions occurring at least 3% more frequently than on placebo are mild local reactions at the site of injection. (6)To report SUSPECTED ADVERSE REACTIONS, contact Merz North America, Inc. at 1-844-469-6379 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In controlled randomized clinical trials, Asclera has been administered to 401 patients with small or very small varicose veins (reticular and spider veins) and compared with another sclerosing agent and with placebo. Patients were 18 to 70 years old. The patient population was predominately female and consisted of Caucasian and Asian patients.Table shows adverse events more common with Asclera or sodium tetradecyl sulfate (STS) 1% than with placebo by at least 3% in the placebo-controlled EASI study [see Clinical Studies (14)]. All of these were injection site reactions and most were mild.Table 1: Adverse Reactions in EASI-studyASCLERA (180 patients)STS 1% (105 patients)Placebo (53 patients)Injection site haematoma42%65%19%Injection site irritation41%73%30%Injection site discoloration38%74%4%Injection site pain24%31%9%Injection site pruritus19%27%4%Injection site warmth16%21%6%Neovascularisation8%20%4%Injection site thrombosis6%1%0%Ultrasound examinations at one week (+-3 days) and 12 weeks (+-2 weeks) after treatment did not reveal deep vein thrombosis in any treatment group.. 6.2Post-marketing Safety Experience The following adverse reactions have been reported during use of polidocanol in world-wide experience. Because these reactions are reported voluntarily from population of uncertain size and without control group, it is not possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Immune system disorders: Anaphylactic shock, angioedema, urticaria generalized, asthmaNervous system disorders: Cerebrovascular accident, migraine, paresthesia (local), loss of consciousness, confusional state, dizzinessCardiac disorders: Cardiac arrest, palpitationsVascular disorders: Deep vein thrombosis, pulmonary embolism, syncope vasovagal, circulatory collapse, vasculitisRespiratory, thoracic and mediastinal disorders: DyspneaSkin and subcutaneous tissue disorders: Skin hyperpigmentation, dermatitis allergic, hypertrichosis (in the area of sclerotherapy)General disorders and injection site conditions: Injection site necrosis, pyrexia, hot flushInjury, poisoning and procedural complications: Nerve injury.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Asclera was evaluated in multicenter, randomized, double-blind, placebo- and comparator-controlled trial (EASI-study) in patients with spider or reticular varicose veins. total of 338 patients were treated with Asclera [0.5% for spider veins (n=94), 1% for reticular veins (n=86)], sodium tetradecyl sulfate (STS) 1% (n=105), or placebo (0.9% isotonic saline solution) (n=53) for either spider or reticular veins. Patients were predominately female, ranging in age from 19 to 70 years. All of them received an intravenous injection in the first treatment session; repeat injections were given three and six weeks later if the previous injection was evaluated as unsuccessful (defined as 1, or on 5-point scale, see below). Patients returned at 12 and 26 weeks after the last injection for final assessments.The primary effectiveness endpoint was improvement of veins judged by blinded panel. Digital images of the selected treatment area were taken prior to injection, compared with those taken at 12 weeks post-treatment, and rated on 5-point scale (1 worse than before, = same as before, = moderate improvement, = good improvement, = complete treatment success); results are shown in Table 2.Table 2: Improvement of veins in digital photographs after 12 weeks and 26 weeksTreatment GroupPolidocanol (n=155)STS (n=105)Placebo (n=53)Digital Photograph Scores at 12 weeksMean +- SD4.5p <0.0001 compared to placebo (Wilcoxon-Mann-Whitney test) +- 0.74.5+- 0.72.2 +- 0.7Digital Photograph Scores at 26 weeksMean +- SD4.5 +- 0.74.5+- 0.82.2 +- 0.7The secondary efficacy criterion was the rate of treatment success, pre-defined as score of or with patients scoring 1, 2, or considered treatment failures; results are shown in Table 3.Table 3: Treatment success rates at 12 weeks and 26 weeksTreatment SuccessTreatment success: Yes= Grade to 5, No= Grade to 3; derived from median of evaluation; Polidocanol (n=155)STS (n=105)Placebo (n=53)At 12 weeks (Visit 4) Yes 95%p<0.0001 compared to placebo. 92% 8%No 5%8%92%Missing 0.6%0%0%At 26 weeks (Visit 5) Yes 95% 91% 6%No 5%9%94%At 12 and 26 weeks, patients judgement of the results was assessed by showing them the digital images of their treatment area taken at baseline and asking them to rate their satisfaction with their treatment using verbal rating scale (1 very unsatisfied; = somewhat unsatisfied; = slightly satisfied; = satisfied and = very satisfied); results are shown in Table 4.Table 4: Patient satisfaction after 12 weeks and 26 weeksPolidocanol (N=155)STS (N=105)Placebo (N=53)Patient satisfaction with treatment after 12 weeks (Visit 4)Satisfied or very satisfied87%p <0.0001 compared to STS and placebo 64%14%Patient satisfaction with treatment after 26 weeks (Visit 5)Satisfied or very satisfied84% 63%16%.

DESCRIPTION SECTION.

11 DESCRIPTION. Asclera is sterile, nonpyrogenic, and colorless to faintly greenish-yellow solution of polidocanol for intravenous use as sclerosing agent.The active ingredient, polidocanol is non-ionic detergent, consisting of two components, polar hydrophilic (dodecyl alcohol) and an apolar hydrophobic (polyethylene oxide) chain. Polidocanol has the following structural formula:C12H25(OCH2CH2)nOH Polyethylene glycol monododecyl ether Mean extent of polymerization (n) Approximately Mean molecular weight Approximately 600Each mL contains mg (0.5%) or 10 mg (1.0%) polidocanol in water for injection with 5% (v/v) ethanol at pH 6.5-8.0; disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate are added for pH adjustment.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter is seen or if the contents of the vial are discolored or if the vial is damaged in any way.For spider veins (varicose veins <=1 mm in diameter), use Asclera 0.5%. For reticular veins (varicose veins to mm in diameter), use Asclera 1%. Use 0.1 to 0.3 mL per injection and no more than 10 mL per session.Use syringe (glass or plastic) with fine needle (typically, 26- or 30-gauge). Insert the needle tangentially into the vein and inject the solution slowly while the needle is still in the vein. Apply only gentle pressure during injection to prevent vein rupture. After the needle has been removed and the injection site has been covered, apply compression in the form of stocking or bandage. After the treatment session, encourage the patient to walk for 15 to 20 minutes. Keep the patient under observation to detect any anaphylactic or allergic reaction [see Warnings and Precautions (5.3)].Maintain compression for to days after treatment of spider veins and for to days for reticular veins. For extensive varicosities, longer compression treatment with compression bandages or gradient compression stocking of higher compression class is recommended. Post-treatment compression is necessary to reduce the risk of deep vein thrombosis.Repeat treatments may be necessary if the extent of the varicose veins requires more than 10 mL. These treatments should be separated by to weeks.Small intravaricose thrombi that develop may be removed by microthrombectomy.. For intravenous use only. Solution strength and the volume injected depend on the size and extent of the varicose veins. Extensive varicosities may require multiple treatment sessions. (2)Spider veins (varicose veins <=1 mm in diameter): Use Asclera 0.5%. (2)Reticular veins (varicose veins to mm in diameter): Use Asclera 1%. (2)Use 0.1 to 0.3 mL for each injection into each varicose vein. The maximum recommended volume per treatment session is 10 mL. (2).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Asclera(R) (polidocanol) is indicated to sclerose uncomplicated spider veins (varicose veins <=1 mm in diameter) and uncomplicated reticular veins (varicose veins to mm in diameter) in the lower extremity. Asclera has not been studied in varicose veins more than mm in diameter.. Asclera (polidocanol) is sclerosing agent indicated to sclerose uncomplicated spider veins (varicose veins <=1 mm in diameter) and uncomplicated reticular veins (varicose veins to mm in diameter) in the lower extremity. Asclera has not been studied in varicose veins more than 3mm in diameter. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to wear compression stockings or support hose on the treated legs continuously for to days and for to weeks during the daytime. Compression stockings or support hose should be thigh or knee high depending upon the area treated in order to provide adequate coverage.Advise the patient to walk for 15 to 20 minutes immediately after the procedure and daily for the next few days.For two to three days following treatment, advise the patient to avoid heavy exercise, sunbathing, long plane flights, and hot baths or sauna.Distributed by:Merz North America, Inc. 6501 Six Forks Road Raleigh, NC 27615Manufactured by: Chemische Fabrik Kreussler Co. GmbH 65203 Wiesbaden GERMANYAsclera is registered trademark of Chemische Fabrik Kreussler Co. GmbH, 65203 Wiesbaden, GERMANY.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate carcinogenic potential have not been conducted with polidocanol. Polidocanol was negative in bacterial reverse mutation assays in Salmonella and E. coli, and in micronucleus assay conducted in mice. Polidocanol induced numerical chromosomal aberrations in cultured newborn Chinese hamster lung fibroblasts in the absence of metabolic activation.Polidocanol did not affect reproductive performance (fertility) of rats when administered intermittently at dosages up to 10 mg/kg (approximately equal to the maximum human dose on the basis of body surface area).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe available data from case reports on use of polidocanol-containing products, including ASCLERA, in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Although none of these risks have been identified, there is minimal benefit in treating uncomplicated spider veins and reticular veins in the lower extremity during pregnancy and lower extremity varicosities that develop during pregnancy as they may spontaneously regress postpartum. The animal reproduction studies were conducted in manner to achieve systemic exposure, while the intended clinical use is local exposure at the injection site with minimal to no systemic exposure; therefore, these data are not relevant to the intended clinical use (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataDevelopmental reproductive toxicity testing was performed in rats and rabbits with intravenous administration. Polidocanol induced maternal and fetal toxicity in rabbits, including reduced mean fetal weight and reduced fetal survival, when administered during gestation days 6-20 at doses of and 10 mg/kg, but it did not cause skeletal or visceral abnormalities. No adverse maternal or fetal effects were observed in rabbits at dose of mg/kg. No evidence of teratogenicity or fetal toxicity was observed in rats dosed during gestation days 6-17 with doses up to 10 mg/kg. Polidocanol did not affect the ability of rats to deliver and rear pups when administered intermittently by intravenous injection from gestation day 17 to post-partum day 21 at doses up to 10 mg/kg. These studies were conducted in manner to achieve systemic exposure, while the intended clinical use is local exposure at the injection site with minimal to no systemic exposure; therefore, these data are not relevant to the intended clinical use.

SPL UNCLASSIFIED SECTION.

5.1Anaphylaxis. Severe allergic reactions have been reported following polidocanol use, including anaphylactic reactions, some of them fatal. Severe reactions are more frequent with use of larger volumes (> mL). Minimize the dose of polidocanol. Be prepared to treat anaphylaxis appropriately. Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, take care in intravenous needle placement and use the smallest effective volume at each injection.After the injection session is completed, apply compression with stocking or bandage, and have the patient walk for 15-20 minutes. Keep the patient under supervision during this period to treat any anaphylactic or allergic reaction [see Dosage and Administration (2)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe available data from case reports on use of polidocanol-containing products, including ASCLERA, in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Although none of these risks have been identified, there is minimal benefit in treating uncomplicated spider veins and reticular veins in the lower extremity during pregnancy and lower extremity varicosities that develop during pregnancy as they may spontaneously regress postpartum. The animal reproduction studies were conducted in manner to achieve systemic exposure, while the intended clinical use is local exposure at the injection site with minimal to no systemic exposure; therefore, these data are not relevant to the intended clinical use (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataDevelopmental reproductive toxicity testing was performed in rats and rabbits with intravenous administration. Polidocanol induced maternal and fetal toxicity in rabbits, including reduced mean fetal weight and reduced fetal survival, when administered during gestation days 6-20 at doses of and 10 mg/kg, but it did not cause skeletal or visceral abnormalities. No adverse maternal or fetal effects were observed in rabbits at dose of mg/kg. No evidence of teratogenicity or fetal toxicity was observed in rats dosed during gestation days 6-17 with doses up to 10 mg/kg. Polidocanol did not affect the ability of rats to deliver and rear pups when administered intermittently by intravenous injection from gestation day 17 to post-partum day 21 at doses up to 10 mg/kg. These studies were conducted in manner to achieve systemic exposure, while the intended clinical use is local exposure at the injection site with minimal to no systemic exposure; therefore, these data are not relevant to the intended clinical use.. 8.2 Lactation. Risk SummaryThere are no data on the presence of polidocanol in human milk, the effects on the breastfed infant, or the effects on milk production. lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk up to hours after ASCLERA administration in order to minimize exposure to breastfed infant.. 8.4 Pediatric Use. The safety and effectiveness of Asclera in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of Asclera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Be prepared to treat anaphylaxis. (5.1)Venous Thrombosis and Pulmonary Embolism. (5.2)Arterial Embolism. (5.3)Tissue ischemia and necrosis: Do not inject intra-arterially. (5.4). Be prepared to treat anaphylaxis. (5.1). Venous Thrombosis and Pulmonary Embolism. (5.2). Arterial Embolism. (5.3). Tissue ischemia and necrosis: Do not inject intra-arterially. (5.4). 5.1Anaphylaxis. Severe allergic reactions have been reported following polidocanol use, including anaphylactic reactions, some of them fatal. Severe reactions are more frequent with use of larger volumes (> mL). Minimize the dose of polidocanol. Be prepared to treat anaphylaxis appropriately. Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, take care in intravenous needle placement and use the smallest effective volume at each injection.After the injection session is completed, apply compression with stocking or bandage, and have the patient walk for 15-20 minutes. Keep the patient under supervision during this period to treat any anaphylactic or allergic reaction [see Dosage and Administration (2)].. 5.2 Venous Thrombosis and Pulmonary Embolism Asclera can cause venous thrombosis and subsequent pulmonary embolism or other thrombotic events. Follow administration instructions closely and monitor for signs of venous thrombosis after treatment. Patients with reduced mobility, history of deep vein thrombosis or pulmonary embolism, or recent (within months) major surgery, prolonged hospitalization or pregnancy are at increased risk for developing thrombosis.. 5.3 Arterial Embolism. Stroke, transient ischemic attack, myocardial infarction, and impaired cardiac function have been reported in close temporal relationship with polidocanol administration. These events may be caused by air embolism when using the product foamed with room air (high nitrogen concentration) or thromboembolism. The safety and efficacy of polidocanol foamed with room air has not been established and its use should be avoided.. 5.4 Tissue Ischemia and Necrosis. Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene. Take care in intravenous needle placement and use the smallest effective volume at each injection site. After the injection session is completed, apply compression with stocking or bandage and have patients walk for 15-20 minutes. If intra-arterial injection of polidocanol occurs, consult vascular surgeon immediately.