Asclera

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

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 1 to 3 mm in diameter), use Asclera 1%. Use 0.1 to 0.3 mL per injection and no more than 10 mL per session. Use a syringe (glass or plastic) with a 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 a 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 2 to 3 days after treatment of spider veins and for 5 to 7 days for reticular veins. For extensive varicosities, longer compression treatment with compression bandages or a gradient compression stocking of a 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 1 to 2 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 1 to 3 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 )

3 DOSAGE FORMS AND STRENGTHS Asclera (polidocanol) is an injection for intravenous use and is available as follows: • 0.5% [10 mg/2 mL (5 mg/mL)] solution in 2 mL single-dose glass ampule • 1% [20 mg/2 mL (10 mg/mL)] solution in 2 mL single-dose glass ampule 0.5% and 1% solution in 2 mL glass ampules. ( 3 )

4 CONTRAINDICATIONS Asclera is contraindicated for patients with known allergy to polidocanol and patients with acute thromboembolic diseases. Known allergies to polidocanol. ( 4 ) Patients with acute thromboembolic diseases. ( 4 )

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 Methapharm at 1-866-701-4636 or medinfo@methapharm.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In 5 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 1 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-study ASCLERA (180 patients) STS 1% (105 patients) Placebo (53 patients) Injection site haematoma 42% 65% 19% Injection site irritation 41% 73% 30% Injection site discoloration 38% 74% 4% Injection site pain 24% 31% 9% Injection site pruritus 19% 27% 4% Injection site warmth 16% 21% 6% Neovascularisation 8% 20% 4% Injection site thrombosis 6% 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. 6.2 Post-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 a population of uncertain size and without a control group, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Immune system disorders: Anaphylactic shock, angioedema, urticaria generalized, asthma Nervous system disorders: Cerebrovascular accident, migraine, paresthesia (local), loss of consciousness, confusional state, dizziness Cardiac disorders: Cardiac arrest, palpitations Vascular disorders: Deep vein thrombosis, pulmonary embolism, syncope vasovagal, circulatory collapse, vasculitis Respiratory, thoracic and mediastinal disorders: Dyspnea Skin 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 flush Injury, poisoning and procedural complications : Nerve injury

7 DRUG INTERACTIONS No drug-drug interactions have been studied with Asclera.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The 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 a 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 a 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 2 to 4% and 15 to 20%, respectively. Data Animal Data Developmental 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 4 and 10 mg/kg, but it did not cause skeletal or visceral abnormalities. No adverse maternal or fetal effects were observed in rabbits at a dose of 2 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 a 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 Summary There are no data on the presence of polidocanol in human milk, the effects on the breastfed infant, or the effects on milk production. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk up to 8 hours after ASCLERA administration in order to minimize exposure to a 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.

12.1 Mechanism of Action The active ingredient of Asclera is polidocanol. Polidocanol is a 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, a dense network of platelets, cellular debris, and fibrin occludes the vessel. Finally, the occluded vein is replaced with connective fibrous tissue.

11 DESCRIPTION Asclera is a sterile, nonpyrogenic, and colorless to faintly greenish-yellow solution of polidocanol for intravenous use as a sclerosing agent. The active ingredient, polidocanol is a non-ionic detergent, consisting of two components, a polar hydrophilic (dodecyl alcohol) and an apolar hydrophobic (polyethylene oxide) chain. Polidocanol has the following structural formula: C 12 H 25 (OCH 2 CH 2 ) n OH Polyethylene glycol monododecyl ether Mean extent of polymerization (n) : Approximately 9 Mean molecular weight : Approximately 600 Each mL contains 5 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 (1.2 mg), potassium dihydrogen phosphate (0.43 mg). chemical structure

10 OVERDOSAGE Overdose may result in a higher incidence of localized reactions such as necrosis.

16 HOW SUPPLIED/STORAGE AND HANDLING Asclera (polidocanol) injection is a colorless to faintly greenish-yellow solution supplied in single-dose, sterile, preservative free ampules in the following packages: NDC 67850-140-05 Five 0.5 % ampules [10 mg/2 mL (5 mg/mL)] NDC 67850-141-05 Five 1 % ampules [20 mg/2 mL (10 mg/mL)] Each ampule is intended for immediate use in a single patient. Each unopened ampule is stable up to three years. Store at 15°C to 30°C; (59°F to 86°F).