ASCLERA
-
laureth-9 injection, solution
Merz Aesthetics, Inc.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use see full prescribing information for and Initial U.S. Approval
|
INDICATIONS AND USAGE
|
Asclera (polidocanol) is a sclerosing agent indicated to treat uncomplicated spider veins (varicose veins less than or equal to 1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. It has not been studied in larger varicose veins greater than 3 mm in diameter. (1)
|
DOSAGE AND ADMINISTRATION
|
For intravenous use only. The strength of the solution 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 to 3 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)
|
DOSAGE FORMS AND STRENGTHS
|
0.5% and 1% solution in 2mL glass ampules. (3)
|
CONTRAINDICATIONS
|
Patients with known allergies to polidocanol. (4)
Patients with acute thromboembolic diseases. (4)
|
WARNINGS AND PRECAUTIONS
|
Be prepared to treat anaphylaxis. (5.1) Do not inject intra-arterially. (5.2) Do not inject intra-perivascularily. (5.3)
|
ADVERSE REACTIONS
|
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 Aesthetics, Inc. at 1-866-862-1211 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION AND FDA-approved patient labelling.
Revised: March/2010
|
|
Revised: 01/2011 |
|
FULL PRESCRIBING INFORMATION: CONTENTS* |
|
|
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Asclera
(R) (polidocanol) is indicated to sclerose uncomplicated spider veins (varicose veins less than or equal to 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.
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 of the vial is damaged in any way.
For spider
veins (varicose veins less than or equal to 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]).
Maintain
compression for 2 to 3 days after treatment of spider veins and 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 require more than 10 mL. These treatments should
be separated by 1 to 2 weeks.
Small intravaricose blood clots
(thrombi) that develop may be removed by stab incision and thrombus
expression (microthrombectomy).
3 DOSAGE FORMS AND STRENGTHS
Asclera is available as a 0.5% and 1% solution in 2 mL glass ampules.
4 CONTRAINDICATION
Asclera
is contraindicated for patients with known allergy (anaphylaxis) to
polidocanol and patients with acute thromboembolic diseases.
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylaxis
Severe
allergic reactions have been reported following polidocanol use,
including anaphylactic reactions, some them fatal. Severe reactions are
more frequent with use of larger volumes (greater than 3 mL). The dose
of polidocanol should therefore be minimized. Be prepared to treat
anaphylaxis appropriately.
Severe adverse local
effects, including tissue necrosis, may occur following extravasation;
therefore, care should be taken in intravenous needle placement and the
smallest effective volume at each injection site should be used.
After
the injection session is completed, apply compression with a 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 Accidental Intra-arterial Injection
Intra-arterial injection can cause severe necrosis, ischemia or gangrene. If this occurs consult a vascular surgeon immediately.
5.3 Inadvertent Perivascular Injection
Inadvertent
perivascular injection of Asclera can cause pain. If pain is severe, a
local anesthetic (without adrenaline) may be injected.
6 ADVERSE REACTIONS
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
predominantly 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 (plus or minus 3 days) and 12 weeks (plus or
minus 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 the use of
polidocanol in world-wide experience; in some of these cases these
adverse events have been serious or troublesome. Because these
reactions are reported voluntarily from a population of uncertain size
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
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
Pregnancy
Category C. Polidocanol has been shown to have an embryocidal effect in
rabbits when given in doses approximately equal (on the basis of body
surface area) to the human dose. This effect may have been secondary to
maternal toxicity. There are no adequate and well controlled studies in
pregnant women. Asclera should not be used during pregnancy.
Animal Studies
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 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.
Human Studies
There are no adequate and well-controlled studies on the use of Asclera in pregnant women.
8.2 Labor and Delivery
The effects of Asclera on labor and delivery in pregnant women are unknown.
8.3 Nursing Mothers
It
is not known whether polidocanol is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants, avoid administering to a
nursing woman.
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.
10 OVERDOSAGE
Overdose may result in a higher incidence of localized reactions such as necrosis.
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 hydrophillic (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 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, potassium dihydrogen phosphate are added for pH
adjustment.
12 CLINICAL PHARMACOLOGY
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.
12.2 Pharmacodynamics
Polidocanol has a 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 a 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term
studies to evaluate carcinogenic potential have not been conducted with
polidocanol. Poliodocanol was negative in bacterial reverse mutation
assays in Salmonella and E. Coli, and in micronucleus assay conducted
in mice. Polidocanol induced numerical chromosonal 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).
14 CLINICAL STUDIES
Asclera was
evaluated in a multicenter, randomized, double-blind, placebo and
comparator controlled trial (EASI-study) in patients with spider or
reticular varicose veins. A 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 predominantly female, ranging in age from 19 to 70 years old. All
of them received an intravenous injection in the first treatment
session; repeat injections were given three to six weeks later if the
previous injection was evaluated as unsuccessful (defined as 1, 2, or 3
on a 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 judges by a 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 a 5-point scale (1 = worse than before, 2 = same as before, 3
= moderate improvement, 4 = good improvement, 5 = complete treatment
success_; results are shown in Table 2.
Table 2: Improvement of veins in digital photographs after 12 weeks and 26
Treatment Group | Polidocanol (n=155) | STS (n=105) | Placebo (n=53) |
Digital Photograph Scores at 12 Weeks |
|
|
|
Mean + SD | 4.5* + 0.7
| 4.5* + 0.7 | 2.2 + 0.7
|
Digital Photograph Scores at 26 Weeks |
|
|
|
Mean + SD | 4.5* + 0.7 | 4.5* + 0.8 | 2.2 + 0.7 |
*p less than 0.0001 compared to placebo (Wilcoxon-Mann-Whitney test)
The
secondary efficacy criterion was the rate of treatment success,
pre-defined as a score of 4 or 5 with patients scoring 1, 2, or 3
considered treatment failures; results are shown in Table 3.
Table 3: Treatment success rates at 12 weeks and 26 weeks
Treatment success?* | Polidocanol (n=155) | STS (n=105) | Placebo (n=53) |
At 12 weeks (Visit 4) |
|
|
|
Yes | 95%**
| 92%**
| 8%
|
No | 5%
| 8%
| 92%
|
Missing | 0.6%
| 0%
| 0%
|
At 26 weeks (Visit 5) |
|
|
|
Yes | 95%**
| 91%**
| 6%
|
No | 5%
| 9%
| 94%
|
*Treatment
success: Yes = Grade 4 to 5, no = Grade 1 to 3; derived from median of
evaluation; **p less than 0.0001 compared to placebo.
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 a
verbal rating scale (1 = very unsatisfied, 2 = somewhat satisfied, 3 =
slightly satisfied, 4 = satisfied, and 5 = very satisfied); results are
shown in Table 4.
Table 4: Patient satisfaction after 12 weeks and 26 weeks
| Polidocanol (n=155) | STS (n=105) | Placebo (n=53) |
Patient satisfaction with treatment after 12 weeks (Visit 4) |
|
|
|
Satisfied or very satisfied | 87%*
| 64%
| 14%
|
Patient satisfaction with treatment after 26 weeks (Visit 5) |
|
|
|
Satisfied or very satisfied | 84%*
| 63%
| 16%
|
*p less than 0.0001 compared to STS and placebo
16 HOW SUPPLIED/STORAGE AND HANDLING
Asclera is supplied in single use, preservative free ampules in the following packages:
NDC 46783-121-52 Five 0.5% ampules (2 mL)
NDC 46783-221-52 Five 1.0% ampules (2 mL)
Each ampule is intended for immediate use in a single patient. Each unopened ampule is stable up to three years.
Store at 15-30 degrees Celsius; (59-86 degrees Fahrenheit).
17 PATIENT COUNSELING INFORMATION
Advise patient to wear compression stockings or support hose on the treated legs continuously for 2 to 3 days and for 2 to 3 weeks during the daytime. Compression stockings or support hose should be thigh or knee high depending on the area treated in order to provide adequate coverage.
Advise 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.
ASCLERA
laureth-9
injection, solution |
|
|
|
|
|
ASCLERA
laureth-9
injection, solution |
|
|
|
|
|
Revised: 01/2011Merz Aesthetics, Inc.