Varithena

1 INDICATIONS AND USAGE VARITHENA (polidocanol injectable foam) is indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein (GSV) system above and below the knee. VARITHENA improves the symptoms of superficial venous incompetence and the appearance of visible varicosities. VARITHENA (polidocanol injectable foam) is a sclerosing agent indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein (GSV) system above and below the knee. VARITHENA improves the symptoms of superficial venous incompetence and the appearance of visible varicosities. ( 1 ).

2 DOSAGE AND ADMINISTRATION For intravenous use only. VARITHENA is intended for intravenous injection using ultrasound guidance, administered via a single cannula into the lumen of the target incompetent trunk veins or by direct injection into varicosities. Use up to 5 mL per injection and no more than 15 mL per session. Physicians administering VARITHENA must be experienced with venous procedures and be trained in the administration of VARITHENA. Activate VARITHENA using the VARITHENA oxygen canister and polidocanol canister ( see Instructions for Use ). Once a VARITHENA transfer unit is in place, foam can be generated and transferred to a syringe. Discard the syringe contents if there are any visible bubbles. Administer the injectable foam within 75 seconds of extraction from the canister to maintain injectable foam properties. Use a new sterile syringe after each injection. Use a new VARITHENA transfer unit for each treatment session. Local anesthetic may be administered prior to cannula insertion but neither tumescent anesthesia nor patient sedation is required. Cannulate the vein to be treated using ultrasound guidance to confirm venous access. Inject freshly generated VARITHENA injectable foam slowly (approximately 1 mL/second in the GSV and 0.5 mL/second in accessory veins or varicosities) while monitoring using ultrasound. Confirm venospasm of the treated vein using ultrasound. When treating the proximal GSV, stop the injection when VARITHENA is 3-5 cm distal to the saphenofemoral junction (SFJ). Apply compression bandaging and stockings and have the patient walk for at least 10 minutes, while being monitored. Maintain compression for 2 weeks after treatment. Repeat treatment may be necessary if the size and extent of the veins to be treated require more than 15 mL of VARITHENA. Separate treatment sessions by a minimum of 5 days. Retained coagulum may be removed by aspiration (microthrombectomy) to improve comfort and reduce skin staining. Incompetent great saphenous or accessory saphenous veins: Use Varithena 1% (CEAP Class 2-6 Disease). ( 2 ). For intravenous use which should be performed under ultrasound guidance when treating the GSV. Use up to 5 mL per injection and 15 mL per treatment session. ( 2 ) Separate treatment sessions by a minimum of 5 days. ( 2 )

3 DOSAGE FORMS AND STRENGTHS VARITHENA is available in the following presentations: 180 mg/18 mL (10 mg/mL) Once activated, VARITHENA is a white, injectable foam delivering a 1% polidocanol solution. Each mL of VARITHENA injectable foam contains 1.3 mg of polidocanol VARITHENA is supplied as polidocanol solution (10 mg/mL) in 18 mL; and must be activated before use. ( 3 ) Once activated, VARITHENA is a white, injectable foam delivering the polidocanol solution. ( 3 ) Each mL of VARITHENA injectable foam contains 1.3 mg of polidocanol.

4 CONTRAINDICATIONS The use of VARITHENA is contraindicated in patients with: known allergy to polidocanol [see Warnings and Precautions ( 5.1 )] acute thromboembolic disease Known allergy to polidocanol ( 4 ) Acute thromboembolic disease ( 4 )

6 ADVERSE REACTIONS In clinical trials, the most common related adverse events (occurring in ≥3% of patients treated with VARITHENA) were pain/discomfort in extremity, infusion site thrombosis (retained coagulum), injection site hematoma or pain, thrombophlebitis superficial, and extravasation.( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocompatibles, Inc. at 1-855-971-VEIN (1-855-971-8346) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of VARITHENA cannot be directly compared to rates in the clinical trials of other drugs or procedures and may not reflect the rates observed in practice. A total of 1333 patients with GSVI in 12 clinical trials were evaluated for safety when treated with VARITHENA at dose concentrations of 0.125%, 0.5%, 1.0%, or 2.0%, including 437 patients treated with VARITHENA in placebo-controlled clinical trials. Adverse reactions occurring in 3% more patients receiving VARITHENA 1% than receiving placebo are shown in Table 1 . a Retained coagulum. b Common femoral vein thrombus extension (non-occlusive thrombi starting in the superficial vein and extending into the common femoral vein). Table 1: Treatment-emergent adverse reactions (3% more on VARITHENA 1% than on placebo) through Week 8 (n=588) Adverse Reaction Placebo (N=151) VARITHENA 1.0% (N=149) Pain in extremity 14 (9.3) 25 (16.8) Infusion site thrombosis b 0 24 (16.1) Contusion/injection site hematoma 9 (6.0) 23 (15.4) Limb discomfort 5 (3.3) 18 (12.1) Tenderness/injection site pain 5 (3.3) 16 (10.7) Venous thrombosis limb c 0 12 (8.1) Thrombophlebitis superficial 2 (1.3) 8 (5.4) Deep vein thrombosis 0 7 (4.7) In VARITHENA-treated patients, 80% of pain events in the treated extremity resolved within 1 week. Proximal symptomatic venous thrombi occurred in <1% of patients treated with VARITHENA. Approximately half of patients with thrombi received treatment with anticoagulants. Since VARITHENA induces thrombosis in the treated superficial veins, D-dimer is commonly elevated post-treatment and is not useful diagnostically to assess patients for venous thrombus following treatment with VARITHENA. Neurologic adverse events (cerebrovascular accident, migraines) have been reported in patients following administration of physician compounded foam sclerosants. None of the 1333 patients in the VARITHENA trials experienced clinically important neurological or visual adverse events suggestive of cerebral gas embolism. The incidence of neurologic and visual adverse events within 1 day of treatment in the placebo-controlled studies was 2.7% in the pooled VARITHENA group and 4.0% in the placebo groups. Skin discoloration adverse events were reported in 1.1% of the pooled VARITHENA group and 0.7% of the placebo group in the placebo-controlled studies.

7 DRUG INTERACTIONS No specific drug interaction studies have been performed. There are no known drug interactions with VARITHENA. There are no known drug interactions with VARITHENA. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Few published case reports with use of polidocanol-containing products, including VARITHENA, in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Although no risks have been identified, there is minimal benefit in treating lower extremity varicosities during pregnancy and lower extremity varicosities that develop during pregnancy as they may spontaneously regress postpartum. In animal reproduction studies, no adverse developmental effects were observed with intravenous administration of polidocanol to pregnant rats and rabbits during organogenesis at dose levels up to approximately 13.5 and 12 times, respectively, the proposed maximum human dose of 15 mL of 1% VARITHENA based on body surface area (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 using intravenous administration of polidocanol solution. In rabbits, dose levels up to and including 10 mg/kg/day (approximately 12 times the proposed maximum human dose of 15 mL of 1% VARITHENA based on body surface area) did not produce any indication of adverse effects on embryo-fetal mortality, fetal weight, or the incidences of fetal abnormalities and variants. In rats administered 27 mg/kg/day of polidocanol solution (approximately 13.5 times the human dose based on body surface area), there were no adverse effects on pregnancy performance or fetal development. In a peri-natal and post-natal study in rats, dose levels of polidocanol up to 9 mg/kg/day (approximately 4.5 times the human dose based on body surface area) were without effects on the development of the conceptus and offspring, and at a dose level of 27 mg/kg/day of polidocanol solution (approximately 13.5 times the human dose based on body surface area), effects were confined to an equivocal reduction in body weights of first-generation males, and an associated equivocal delay in the age of preputial separation. 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 anddiscarding breast milk up to 8 hours after VARITHENA administration in order to minimize exposure to a breastfed infant. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 1333 subjects in clinical studies treated with VARITHENA, 9.1% (n=121) were ≥65 years of age. No clinically important differences in safety or efficacy were observed between older and younger patients in all studies.

12.1 Mechanism of Action VARITHENA is a drug/device combination product that generates injectable foam. The injectable foam is composed of a liquid and gas phase, both of which are necessary to have its therapeutic effect. VARITHENA is intended to act as follows: (1) the foam displaces blood from the vein to be treated, and (2) the polidocanol then scleroses the endothelium. The active pharmaceutical ingredient of VARITHENA is polidocanol, a non-ionic surfactant sclerosing agent. The hydrophobic pole of the polidocanol molecule attaches to the lipid cell membrane of the venous endothelium, resulting in disruption of the osmotic barrier, destruction of the venous endothelium, and vasospasm. Following exposure to polidocanol, the interior surface of the vein becomes thrombogenic, which leads to thrombus formation and venous occlusion. The occluded vein is eventually replaced by fibrous connective tissue. Polidocanol is deactivated upon contact with blood, thus limiting the sclerosant action to the endothelium near the site of injection.

11 DESCRIPTION VARITHENA injectable foam contains the sclerosant, polidocanol. It is intended for intravenous use only. Chemically, polidocanol is polyoxyl lauryl ether. The structural formula is represented below: Polidocanol has the molecular formula CH 3 (CH 2 ) 11 (OCH 2 CH 2 ) n OH and a molecular weight of 582.9 when the average ethylene glycol moieties is nine (n=9). Polidocanol is a white to almost white, waxy, hygroscopic solid that is soluble in water and alcohol and melts at temperatures above 20°C. VARITHENA is a sterile, injectable foam of an aqueous polidocanol solution (1%) containing the following inactive ingredients: alcohol (4.2% w/w, purity 96% v/v) disodium hydrogen phosphate dihydrate (0.24% w/w), and potassium dihydrogen phosphate (0.085% w/w) with a pH of 6.0-7.5. The injectable foam is generated after activation of the polidocanol canister with oxygen from a second aluminum canister, resulting in a final gas mixture of oxygen:carbon dioxide in a ratio of 65:35 with low (<0.8%) nitrogen content. At the time of use, VARITHENA is generated as an injectable foam of controlled density and bubble size. The foam is then transferred to a syringe through the VARITHENA transfer unit. The injectable foam has a liquid to gas ratio of approximately 1:7 by volume. The median bubble diameter is less than 100 μm and no bubbles are greater than 500 μm. polidocanol Structural Formula

10 OVERDOSAGE There are no known cases of overdosage with VARITHENA. In clinical studies, total volumes of up to 60 mL of VARITHENA per treatment session have been administered.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VARITHENA (polidocanol injectable foam) product is available in four configurations, each containing two sterile, connected, 303-mL aluminum alloy cylinders, one containing polidocanol solution (10 mg/mL) under carbon dioxide, and the other containing pressurized oxygen. Polidocanol mg Usable foam mL NDC 180 45 60635-118-01 PD Canister - 60635-018-01 16.2 Storage and Handling Do not shake VARITHENA canisters. Avoid contact with eyes. Store the VARITHENA Bi-Canister at or below 86°F (30°C); Do not refrigerate or freeze. Unused, non-activated VARITHENA canisters may be stored in the flat or upright position. Contains gas under pressure: May explode if heated. Store in a well-ventilated place. Store the canisters away from sources of heat including strong light conditions. Pressurized Oxygen: May cause or intensify fire; oxidizer. Store away from combustible materials. Once activated, the canister of 180 mg/18 mL (10 mg/mL) VARITHENA must be used within thirty (30) days. Store activated canisters of VARITHENA upright, with the VARITHENA transfer unit attached, under the same temperature conditions as the VARITHENA Bi-Canister. Use a new VARITHENA transfer unit for each treatment session. Discard aerosol canisters after use in accordance with state and local requirements. For more information, please refer to the IFU.