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Varithena

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Varithena

CLINICAL PHARMACOLOGY

Mechanism Of Action

Varithena™ is 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, (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.

Pharmacodynamics

The active pharmaceutical ingredient in Varithena™ is polidocanol. Polidocanol has a concentration dependent damaging effect on the endothelium of blood vessels.

Pharmacokinetics

The pharmacokinetics of Varithena™ (as a weighted sum of 4 oligomers: E5, E9, E12 and E14) were evaluated at two concentrations (1% and 2%) randomly assigned within gender in 20 patients with GSV incompetence.

When administered as an intravenous injectable foam as two fixed 5 mL doses separated by 10 minutes, polidocanol was rapidly detected in plasma, reaching maximum concentration of drug in the body after dosing (Cmax) within 15 minutes of the first injection and within 5 mins of receiving the second injection of Varithena™ 1% or Varithena™ 2%. The mean volume of distribution (Vd) of polidocanol ranged from 35L to 82L.

Mean systemic clearance (CL) of polidocanol ranged from 0.2 to 0.4 L/min. The clearance of E5 was significantly greater than is that of longer oligomers. Mean terminal elimination half-life (t1/2) ranged from 102 to 153 minutes, with most plasma samples below the limit of quantitation (BLQ) at the end of the 8 hour collection period. The increase in plasma polidocanol concentrations was less than proportional with increasing Varithena™ concentration. Weight normalized data demonstrated no consistent differences in Cmax or AUC between males and females.

Animal Toxicology And/Or Pharmacology

The pharmacological effects of polidocanol solution on the renal function of the rat were evaluated and at the highest dose tested (10 mg/kg) hematuria occurred in 67% of animals. This dose is 5 times higher than the proposed maximum human dose based on body surface area. Blood was no longer detectable in urine 24 hours after dosing. In the 28 day repeated dose toxicity study in rat blood pigments were noted in the urine for animals in all treatment groups, including male controls, at the end of the 4 week treatment period with up to 27 mg polidocanol/kg/day. Following the 2 week recovery period there was still evidence that blood pigments were present in the urine but the incidence and severity was decreased when compared to the main study animals. There were no histopathological findings in the urinary bladder in any study animals.

In a cardiovascular pharmacology study in the anesthetized dog at 20 mg/kg (approximately 33 times the human dose based on body surface area) statistically significantly higher values for P-Q interval were measured before and during dosing and at all time points up to 30 minutes after dosing. An increase in QRS interval was also measured after dosing of 20 mg/kg and at 5 and 10 minutes after dosing. This effect was short lived and was no longer seen at 15 minutes after dosing. In addition, there was an increase in diastolic pressure with increasing dose of polidocanol. This increase became significantly greater (p < 0.05) than baseline before injection of the final and highest dose (20 mg/kg).

In a further cardiovascular pharmacology study conducted with a once weekly, for four weeks, intravenous bolus injection of Varithena™ in the conscious dog, dose levels of up to 8.0 mL/kg (approximately 17 times the human dose based on body surface area) to beagle dogs caused only a transient, but consistent, effect on respiration, evidenced by a decrease in tidal volume and RMV at 15 minutes post-dose, resolving by one hour post-dose. Histopathology of the lung at the end of the 3 month follow-up period showed no abnormalities.

Clinical 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, or 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.

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% Pooled Varithena™* Placebo Varithena™ 1.0% Pooled Varithena™*
N 55 50 164 54 57 117
Baseline score, mean 8.60 8.82 9.23 9.26 7.82 8.67
Adjusted mean change from baseline at week 8 -2.13 -4.87 -5.44 -2.00 -5.06 -5.53
Clinically meaningful improvement in symptoms at week 8** 5.4% (n=56) 64.7% (n=51) 76.4% (n=165) 19.6% (n=56) 75.9% (n=58) 79.7% (n=118)
Comparison vs. Placebo at week 8, p-value, adjusted mean change   < 0.0001 < 0.0001   < 0.0001 < 0.0001
*VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.
**Percent of patients who reported their symptoms had “moderately improved” or “much improved” compared with baseline.

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.

Table 3: Improvement in Appearance of Visible Varicosities as Measured by IPR-V3and PAV3at Week 8, VANISH-1 and VANISH-2

  VANISH-1 VANISH-2
Placebo Varithena™ 1.0% Pooled Varithena™* Placebo Varithena™ 1.0% Pooled Varithena™*
IPR-V3
n 55 49 161 56 57 117
Baseline score, mean 1.82 1.98 2.07 2.18 2.02 2.11
Adjusted mean change from baseline at week 8 -0.01 -0.76 -0.81 -0.07 -0.83 -0.86
Clinically meaningful improvement in appearance at week 8† 8.9% (n=56) 70.6% (n=51) 79.4% (n=165) 0 (n=56) 70.7% (n=58) 72.9% (n=118)
Comparison vs. Placebo, p-value at week 8, adjusted mean change   < 0.0001 < 0.0001   < 0.0001 < 0.0001
PA-V3
N 55 50 164 56 57 117
Baseline score, mean 3.49 3.46 3.54 3.30 3.49 3.54
Adjusted mean change from baseline at week 8 -0.15 -1.60 -1.58 -0.32 -1.79 -1.82
Clinically meaningful improvement in appearance at week 8† 3.6% (n=56) 54.9% (n=51) 64.2% (n=165) 7.1% (n=56) 69.0% (n=58) 74.6% (n=118)
Comparison vs. Placebo, p-value at week 8, adjusted mean change   < 0.0001 < 0.0001   < 0.0001 < 0.0001
*VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.
†Percent who reported the appearance of varicose veins had “moderately improved” or “much improved” compared with baseline.

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.

Table 4: Response to Treatment as Measured by Duplex Ultrasound at Week 8, VANISH-1 and VANISH-2

Parameter Treatment Group, % Comparison of Pooled Varithena™* vs. Varithena™ 0.125%(control)
Placebo Varithena™ 0.125% (control) Varithena™ 1.0% Pooled Varithena™* P-value
Responders, 5.4% 42.1% 80.4% 74.5%  
VANISH-1** (n=56) (n=57) (n=51) (n=165) < 0.0001
Responders, 1.8% 59.6% 86.2% 84.7%  
VANISH-2 (n=56) (n=57) (n=58) (n=118) 0.0002
* VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.
**In VANISH-1, a significant dose-response trend was evident between the percent of responders and the dose concentration of Varithena™ (P < 0.0001).

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.

Last reviewed on RxList: 7/17/2014
This monograph has been modified to include the generic and brand name in many instances.

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