Varithena Dailymed

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)
• 77.5 mg/7.75 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 or 7.75 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)

5 Warnings And Precautions

• Be prepared to treat anaphylaxis. (5.1)
• Tissue ischemia and necrosis: do not inject intra-arterially. (5.2)
• Venous Thrombosis. (5.3)

5.1Anaphylaxis

Severe allergic reactions have been reported following administration of liquid polidocanol, including anaphylactic reactions, some of them fatal. Observe patients for at least 10 minutes following injection and be prepared to treat anaphylaxis appropriately.

5.2Tissue Ischemia and Necrosis

Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene Patients with underlying arterial disease, such as marked peripheral arteriosclerosis or thromboangiitis obliterans (Buerger’s Disease) may be at increased risk for tissue ischemia. If intra-arterial injection of polidocanol occurs, consult a vascular surgeon immediately.

5.3 Venous Thrombosis

VARITHENA can cause venous thrombosis [see Adverse Reactions (6)]. 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 3 months) major surgery, prolonged hospitalization, or pregnancy are at increased risk for developing thrombosis.

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.

6.1Clinical 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 thrombosisb	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 limbc	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.

VARITHENA was evaluated in two randomized, blinded, multicenter clinical trials designed to assess the efficacy and safety of VARITHENA 0.5%, 1.0%, and 2.0% (VANISH-1) and VARITHENA 0.5% and 1.0% (VANISH-2) compared with placebo in the treatment of both symptoms and appearance in patients with SFJ incompetence as evidenced by reflux of the GSV or major accessory veins. In both studies, a VARITHENA 0.125% treatment group was included as a control for blinding of the duplex ultrasound assessment. Patients with history of deep vein thrombosis or pulmonary embolism; inability to comply with post-treatment compression due to severe peripheral arterial disease or leg obesity; incompetence of the small saphenous vein or deep venous reflux as a major source of reflux; or reduced mobility, major surgery, pregnancy, or prolonged hospitalization within 3 months were excluded. Patients were randomized in an equal distribution to each treatment group; the primary time point for analyses of the primary, secondary, and tertiary efficacy endpoints was Week 8.

In these clinical trials, the maximum volume of injectable foam or placebo to be administered per treatment session was 15 mL.

In VANISH-1, patients received one blinded treatment and in VANISH-2, patients received one blinded treatment with an option for a second blinded treatment 1 week later. In VANISH-2, patients in the VARITHENA 1.0% treatment group received an average of 1.4 blinded treatments. All patients received post-procedure compression therapy for 14 days following treatment.

Of the 519 patients randomized into VANISH-1 and VANISH-2, a total of 511 were treated with either VARITHENA 0.5% (n=111), 1.0% (n=110), or 2.0% (n=63), VARITHENA 0.125% as control (n=114), or placebo (n=113). Ninety-nine percent of the patients in VANISH-1 and VANISH-2 completed the blinded treatment period.

In the VARITHENA 1% group in VANISH-2, 23 of 58 patients received an additional blinded treatment. Two of these patients had retreatment of veins treated in the initial treatment session. The remaining 21 patients received treatment for additional veins not treated in the initial treatment session.

The mean age was approximately 50 years and approximately three-fourths of the patients were women. The mean BMI was similar in VANISH-1 and VANISH-2, at 28 kg/m² (range 16 to 44 kg/m²) and 30 kg/m² (range 17 to 48 kg/m²), respectively. The mean baseline GSV diameter was also similar in VANISH-1 and VANISH-2, at 7.6 mm (range 1.5 to 25.9 mm) and 8.7 mm (range 3.1 to 19.4 mm), respectively. Overall, 22% of patients in VANISH-1 and 25% of patients in VANISH-2 reported one or more prior varicose vein procedures in the leg to be treated.

For both clinical trials, the primary efficacy endpoint was improvement in patient symptoms, as measured by the change from baseline to Week 8 in the 7-day average electronic daily diary VVSymQ^® score. The VVSymQ^® score is a patient-reported outcome measure based on daily patient assessment of the varicose vein symptoms determined to be most important to patients: heaviness, achiness, swelling, throbbing, and itching. VVSymQ^® scores range from 0 to 25, where 0 represents no symptoms and 25 represents all 5 symptoms experienced all of the time. Results are shown in Table 2.

For both VANISH-1 and VANISH-2, treatment with 1.0% was superior to placebo in improving symptoms as measured by VVSymQ^®, when either a duration or an intensity scale was used to measure patients’ symptoms.

*Percent of patients who reported their symptoms had "moderately improved" or "much improved" compared with baseline.
Table 2:             Improvement in Symptoms of Varicose Veins as Measured by VVSymQ® at Week 8, VANISH-1 and VANISH-2
	VVSymQ®
	VANISH-1		VANISH-2
	Placebo	VARITHENA 1.0%	Placebo	VARITHENA 1.0%
N	55	50	54	57
Baseline score, mean	8.60	8.82	9.26	7.82
Adjusted mean change  from baseline at week 8	-2.13	-4.87	-2.00	-5.06
Clinically meaningful  improvement in symptoms at   week 8*	5.4%(n=56)	64.7%(n=51)	19.6%(n=56)	75.9%(n=58)
Comparison vs. Placebo at   week 8, p-value, adjusted   mean change		<0.0001		<0.0001

The co-secondary endpoints in VANISH-1 and VANISH-2 were the improvement in appearance of visible varicosities from baseline to Week 8 as measured by 1) patients scoring the appearance of their varicose veins in the medial view of their study leg (PA-V³ score) from "Not at all noticeable" (a score of 0) to "Extremely noticeable" (a score of 4); and 2) an independent photography review panel rating the severity of the patient's varicose vein appearance in standardized digital photographs of the medial view of each patient's study leg (IPR-V³ score) from "None" (a score of 0) to "Very severe" (a score of 4). Results are shown in Table 3.

†Percent who reported the appearance of varicose veins had “moderately improved” or “much improved” compared with  baseline.
Table 3:             Improvement in Appearance of Visible Varicosities as Measured by IPR-V3and PA-V3at Week 8, VANISH-1 and                            VANISH-2
	VANISH-1		VANISH-2
	Placebo	VARITHENA1.0%	Placebo	VARITHENA1.0%
IPR-V3
n	55	49	56	57
Baseline score, mean	1.82	1.98	2.18	2.02
Adjusted mean change from baseline at week 8	-0.01	-0.76	-0.07	-0.83
Clinically meaningful improvement in appearance at week 8†	8.9%(n=56)	70.6%(n=51)	0(n=56)	70.7%(n=58)
Comparison vs. Placebo, p-value at week 8, adjusted mean change		<0.0001		<0.0001
PA-V3
N	55	50	56	57
Baseline score, mean	3.49	3.46	3.30	3.49
Adjusted mean change from baseline at week 8	-0.15	-1.60	-0.32	-1.79
Clinically meaningful improvement inappearance at week 8†	3.6%(n=56)	54.9%(n=51)	7.1%(n=56)	69.0%(n=58)
Comparison vs. Placebo, p-value at week 8, adjusted mean change		<0.0001		<0.0001

Tertiary endpoints in VANISH-1 and VANISH-2 included response to treatment as determined by change from baseline in Venous Clinical Severity Score (VCSS), by duplex ultrasound, and by change from baseline in Venous Insufficiency Epidemiologic and Economic Study – Quality of Life/Symptoms (VEINES-QOL) score.

VCSS is a clinician rating of severity of chronic venous insufficiency ranging from 0 to 30, where higher scores indicate more severe venous disease. In VANISH-1 and VANISH-2, the adjusted mean changes from baseline in VCSS in the 1% VARITHENA treatment groups were 3.70 and 5.05, respectively, at Week 8 compared with 0.75 and 1.52 points in the placebo groups, respectively. For both studies, the differences between these improvements are statistically significant (P<0.0001).

The physiological response to treatment as measured by duplex ultrasound (duplex response) was defined as elimination of reflux through the SFJ and/or complete occlusion of all incompetent GSV and major accessory veins at baseline. The primary comparison for duplex response in both studies was the pooled VARITHENA groups versus the VARITHENA 0.125% (control) group. Results are shown in Table 4.

*In VANISH-1, a significant dose-response trend was evident between the percent of responders and the dose concentration of VARITHENA (P<0.0001).
Table 4:             Response to Treatment as Measured by Duplex Ultrasound at Week 8, VANISH-1 and VANISH-2
Parameter	Treatment Group, %
	Placebo	VARITHENA 0.125% (control)	VARITHENA 1.0%
Responders, VANISH-1*	5.4%(n=56)	42.1%(n=57)	80.4%(n=51)
Responders, VANISH-2	1.8%(n=56)	59.6%(n=57)	86.2%(n=58)

VEINES-QOL is a disease-specific quality of life instrument, ranging from 0 (worst possible quality of life) to 100 (best possible quality of life). In VANISH-1 and VANISH-2, the adjusted mean changes from baseline in VEINES-QOL in the pooled VARITHENA treatment groups were 21.2 and 21.6, respectively, at Week 8 compared with 7.7 and 7.4 points in the placebo groups, respectively. For both studies, the differences between these improvements are statistically significant (P<0.0001).

For efficacy endpoints, VARITHENA treatment effects were consistent across subgroups of age, sex, BMI (up to 48 kg/m²), CEAP clinical class, GSV diameter (up to 25.9 mm), and VCSS.