FIBROVEIN 1% SOLUTION FOR INJECTION - summary of medicine characteristics

Fibrovein 1% Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml solution for injection contains 10 mg sodium tetradecyl sulfate.

Each 2 ml ampoule contains 20 mg sodium tetradecyl sulfate.

Excipient(s) with known effect

Contains benzyl alcohol 20 mg/ml.

Contains sodium up to approximately 1.7 mg/ml.

Contains potassium 0.3 mg/ml.

For the full list of excipients, see section 6.1.

4   CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of uncomplicated primary varicose veins, recurrent or residual varicose veins following surgery, reticular veins, venules and spider veins of the lower extremities that show simple dilation.

Posology

Fibrovein is for intravenous use only. The strength of solution required depends on the size and degree of varicosity. Spider veins should only be treated with the 0.2%, reticular veins with 0.5%, the 1% solution will be found most useful for small to medium varicosities and the 3% solution for larger varicosities. The size of nonvisible varicose veins should be measured under ultrasound.

The sclerosant should be administered intravenously in small aliquots at multiple sites along the vein to be treated either as a liquid or as a sclerosant/air mixture (foam), for the treatment of larger veins with the 1% and 3% solutions. The objective is to achieve optimal destruction of the vessel wall with the minimum concentration of sclerosant necessary for a clinical result. If the concentration is too high necrosis or other adverse sequelae may occur.

Adults

* volume is the sum of the liquid and air components

Where special caution is indicated it is recommended that a test dose of 0.25 to 0.5 ml Fibrovein should be given followed by observation of the patient for several hours before administration of a second or larger dose.

As the volume to be injected is limited per session, repeated sessions are usually needed (2 to 4 on average). To prevent a possible allergic reaction, it is recommended that a small test dose of Fibrovein should be given at the beginning of each session.

When the sclerosant is administered as a foam

Fibrovein 1 % may be converted to a foam to be used for the treatment of larger veins. The foam must be prepared just before use and administered by a physician appropriately trained in the correct generation and administration of foam. It should ideally be administered under ultra sound guidance.

Elderly population

No specific dose recommendations apply.

Paediatric population

The safety and efficacy of Fibrovein in children and adolescents have not been established. No data are available.

The Tessari method of preparation of the foam is described in section 6.6. Other techniques may be used e.g. DSS, Easyfoam and Steriven most of which consist of mixing sclerosant and sterile air by repeated passes through 2 connected syringes. Specific instructions for handling are detailed in section 6.6.

Strict aseptic technique must be maintained while handling Fibrovein.

Fibrovein is a single-use parenteral product. Once the container is opened, use immediately and discard any unused portion.

Visually inspect for particulate matter before use. Solutions that contain particulate matter should not be used.

4.3 Contraindications

Hypersensitivity to active substance or any of the excipients listed in section 6.1 and allergic conditions

Unable to walk due to any cause, bedridden

High risk of thrombosis e.g. a congenital predisposition to blood clots or multiple risk factors such as hormonal contraception or hormone replacement therapy, significant obesity, smoking or extended periods of immobility

Recent acute superficial thrombophlebitis, deep vein thrombosis or pulmonary embolism

Recent surgery

Varicosities caused by pelvic or abdominal tumours unless the tumour has been removed

Uncontrolled systemic disease such as diabetes mellitus, toxic hyperthyroidism, tuberculosis, asthma, neoplasm, sepsis, blood dyscrasias and acute respiratory or skin diseases

Evolutive cancer

Significant valvular incompetence of the deep veins

Occlusive arterial disease

Huge superficial veins with wide open communications to deeper veins

Phlebitis migrans

Acute cellulitis

Acute infections

In addition, when the sclerosant has been converted to foam:

Known symptomatic patent foramen ovale (PFO).

4.4 Special warnings and precautions for use

General precautions

Fibrovein should only be administered by a healthcare professional experienced in venous anatomy and the diagnosis and treatment of conditions affecting the venous system and familiar with proper injection technique.

Emergency resuscitation equipment should be immediately available. Allergic reactions, including anaphylaxis have been reported. The possibility of an anaphylactic reaction should be kept in mind, and the physician should be prepared to treat it appropriately.

Before treatment, healthcare professional should investigate patient’s risk factors and inform them about the risks of the technique.

As a reminder, sclerotherapy is contraindicated in patients with high risk of thromboembolic events, but should also be avoided in most situations at lower risk. Sclerotherapy is notably not recommended in patients with a history of thromboembolic e­vents

Nevertheless, if sclerotherapy is judged necessary, preventive anticoagulation can be initiated.

Patent foramen ovale (PFO)

Due to the risk of circulation of product, bubbles or particulates in the right heart, the presence of a PFO may enhance the occurrence of serious arterial adverse events. In patients with history of migraine with aura, serious cerebrovascular events or pulmonary hypertension, it is recommended to search for PFO before sclerotherapy.

In patients with asymptomatic but known PFO, it is recommended to use smaller volumes and avoid Valsalva manoeuvre in the minutes after injection.

Patients with a PFO have been shown to be more likely to suffer from adverse events such as temporary neurological events, visual disturbances and migraine. A symptomatic PFO is a contraindication for use of Fibrovein as a foam (see section 4.3)

Migraine

Previous migraine sufferers should be treated with care. Patients with previous migraine have been shown to be more likely to suffer from visual disturbances and migraine, particularly following injections with foamed sclerosant.

Use smaller volumes in patients with history of migraine.

Truncular varicosities

For the treatment of truncular varicosities, there should be a minimal distance of 8 to 10 cm between the site of foam injection and the saphenofemoral junction.

Lymphoedema

If venous insufficiency is associated with lymphoedema, the sclerosant injection may worsen local pain and inflammation for days or several weeks. Patients should be informed of this expected phase, which does not compromise efficacy.

Extravasation

Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, extreme care in intravenous needle placement and using the minimal effective volume at each injection site are important. Pigmentation may be more likely to result if blood is extravasated at the injection site (particularly when treating smaller surface veins) and compression is not used.

Intra-arterial injection

Sclerosants must never be injected into an artery as this can cause extended tissue necrosis and may result in loss of the extremity. Injection under duplex ultrasound is recommended in order to avoid extravasations and arterial injection.

Healthcare professional should monitor the patient during and after the administration of Fibrovein. Symptoms of hypersensitivity (redness, pruritus, cough) or neurological symptoms (scotoma, amaurosis, migraine with aura, paraesthesia, focal deficit) may happen.

Respiratory disease

Special care should be taken in patients with laboured breathing (bronchial asthma) or a strong predisposition to allergies (see section 4.2).

Pre-injection evaluation

Because of the danger of thrombosis extension into the deep venous system, thorough pre-injection evaluation for valvular competency should be carried out and slow injections with a small amount (not over 2 mL) of the preparation should be injected into the varicosity. Deep venous patency must be determined by non-invasive testing such as duplex ultrasound. Venous sclerotherapy should not be undertaken if tests such as Trendelenberg and Perthes, and angiography show significant valvular or deep venous incompetence.

Follow-up

Healthcare professional should see the patient again after 1 month for a control of treatment efficacy and safety, by clinical and ultrasound evaluation.

The development of deep vein thrombosis and pulmonary embolism have been reported following sclerotherapy treatment of superficial varicosities. Patients should have post-treatment follow-up of sufficient duration to assess for the development of deep vein thrombosis. Embolism may occur as long as four weeks after injection of sodium tetradecyl sulfate. Adequate post-treatment compression may decrease the incidence of deep vein thrombosis.

Underlying arterial disease

Extreme caution in use is required in patients with underlying arterial disease such as severe peripheral atherosclerosis or thromboangiitis obliterans (Buerger's di­sease).

Foot and malleolar area

Special care is required when injecting the foot and malleolar area where the risk of inadvertent injection into an artery may be increased.

Excipients

This medicinal product contains:

less than 1 mmol sodium (23 mg) per vial/ampoule, i.e. essentially ‘sodium-free’.

less than 1 mmol potassium (39 mg) per vial/ampoule, i.e. essentially ‘potassium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

Safety for use in pregnancy has not been established. There are no or limited amount of data from the use of sodium tetradecyl sulfate in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Treatment should be postponed until after childbirth.

Fibrovein should be used only when clearly needed for symptomatic relief and when the potential benefits outweigh the potential hazards to the fetus.

Breast-feeding

It is not known whether sodium tetradecyl sulfate is excreted in human milk. Caution should be exercised when used in nursing mothers.

Fertility

It is not known whether sodium tetradecyl sulfate affects fertility.

4.7 Effects on ability to drive and use machines

Fibrovein has no or negligible direct influence on the ability to drive and use machines. However, a bandage and/or compression stockings may be added after treatment. This could affect the ability to drive.

4.8 Undesirable effects

The most commonly reported side effects are pain on injection urticaria, superficial thrombophlebitis and temporary skin pigmentation after treatment. Very rarely a permanent discoloration may remain along the path of the sclerosed vein segment. Ulceration may occur following extravasation of the drug. It is important to use the lowest strength that will sclerose the vein as many of the common side effects are caused by using a concentration that is too high.

Intra-arterial injection although very rare has been reported resulting in significant tissue necrosis including loss of the extremity.

The most serious side effects are anaphylactic shock and pulmonary embolism and deaths have been reported in patients receiving sodium tetradecyl sulfate.

Adverse events are listed below by system organ class and estimated frequency from published clinical data. Frequencies are defined using the following convention:

Very common: >1/10

Common: >1/100 to <1/10

Uncommon: >1/1,000 to <1/100

Rare: >1/10,000 to <1/1,000

Very rare: (includes isolated reports) <1/10,000

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No case of systemic overdose has been reported. Using a higher concentration than recommended in small veins may lead to pigmentation and/or local tissue necrosis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vasoprotectives, Sclerosing agents for local injections, ATC code C05BB04.

Sodium tetradecyl sulfate is a sclerosing agent. Intravenous injection causes intima inflammation and thrombus formation. This usually occludes the injected vein.

Subsequent formation of fibrous tissue results in partial or complete vein obliteration that may or may not be permanent.

Published clinical series have shown that Fibrovein converted to a foam is very effective at treating larger varicose veins e.g. great saphenous vein and tributaries. The foam is able to displace the blood and the sclerosant has more time to act on the endothelium compared to the liquid form. Some adverse events are more frequent following foam sclerotherapy than liquid sclerotherapy e.g. headache, migraine and visual disturbances. Adverse neurological events may also occur but these are rare.

5.2 Pharmacokinetic properties

Absorption

Fibrovein containing sodium tetradecyl sulfate is administered directly into the lumen of the isolated segment of vein/venule.

Distribution

In humans, the majority (75 %) of an injected dose of radiolabelled 3 % sodium tetradecyl sulfate rapidly disappeared from the empty varicose vein injection site into communicating blood vessels with rapid passage into the deep calf veins.

In rats, at 72 hours after intravenous dosing of radiolabelled sodium tetradecyl sulfate, tissue levels of radiolabel found in the sampled tissues (liver, kidney, lipid and skeletal muscle) were extremely low. Although there was some evidence of radiolabel associated with the injection site, the levels were very low.

Biotransformation

The metabolism of sodium tetradecyl sulfate has not been confirmed.

Elimination

Of an intravenously administered radiolabelled dose, 70 % was recovered in the urine of rats within the first 24 hours post-dosing. At the end of the 72 hour post-dose period, 73.5 % of the radiolabel had been recovered from the urine and 18.2 % recovered from the faeces.

Hepatic/renal impairment

No pharmacokinetics studies have been performed in patients with hepatic or renal impairment.

5.3 Preclinical safety data

There are no additional data of relevance to the prescriber other than those already mentioned in other sections of the SmPC.

6.1

List of excipients

Benzyl alcohol

Disodium phosphate dodecahydrate

Potassium dihydrogen phosphate

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

This medicinal product is not compatible with heparin.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years.

After first opening, the medicinal product should be used immediately.

6.4 Special precautions for storage

This medicinal product does not require any special temperature conditions (Temperature Zone 1).

Do not store above 25 °C (For all other Temperature zones).

Do not freeze.

Keep the vial/ampoule in the outer carton in order to protect from light.

6.5 Nature and contents of container

2 ml ampoule (Type I glass).

Pack size of 5 ampoules of 2 ml.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Fibrovein 1 % Solution for Injection

The foam must be prepared just before use and administered by a physician appropriately trained in the correct generation and administration of foam.

Strict aseptic technique must be maintained while manufacturing the foam.

General guidelines

The quality of foam depends on specific criteria:

1. The product concentration: Foam can only be prepared with concentrations of 1 to 3 % sodium tetradecyl sulfate.

2. The proportion of liquid to air: Usually, this proportion is 1 volume of liquid for 3 volumes of air.

3. Number of backwards and forwards passes: The physician should follow precisely the number of movements defined for each technique.

4. Macroscopic consistency of the foam: The quality of the foam should be checked outside of the syringe before administration. The foam should be homogenous, soft and cohesive with no visible large bubbles. If large bubbles are visible, the foam should be thrown away and a new foam prepared.

5. The total time of preparation of the foam: The preparation should take around 10 seconds from the first to the last backwards and forwards movement.

6. The maximum time between preparation and injection: The sclerosant foam must be used within sixty seconds of production. After sixty seconds, any remaining foam should be discarded. More foam should be prepared if required.

Manufacture of foam using the Tessari technique

To create the foam 1 ml of liquid sclerosant is drawn into a sterile syringe and 3 ml or 4 ml of sterile air is drawn into another sterile syringe. The air is drawn through a 0.2 qm filter to ensure it is sterile. The syringes are then connected using a sterile three way tap/valve (Fig. 1). The use of Luer lock syringes and eye protection are recommended when making the foam. The connection with the 3-way tap can fail under pressure with Luer slip syringes resulting in product being squirted out uncontrollably.

The sclerosant/air mixture is then forced back and forth from one syringe to the other through the 3-way valve at least 20 times to produce a smooth, consistent foam (Fig. 2&3).

The syringe containing the foam, is then removed and the vein is injected immediately (Fig. 4).

The sclerosant foam must be used within sixty seconds of production. After sixty seconds any remaining foam should be discarded. More foam should be prepared if required.

The quality of the foam should be checked before administration. It should appear homogeneous with no large bubbles visible to the naked eye.

Figure 1

Figure 2

Figure 3

Figure 4

Disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

STD Pharmaceutical Products Ltd

Plough Lane

Hereford

HR4 0EL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00398/0206