Varithena: Uses, Side Effects and Dosage

Serious Warnings and Precautions

• Allergic reaction

Varithena™ is a foam; one of the ingredients is polidocanol. Some people treated with polidocanol have had severe allergic reactions, and some of these people died. After you are treated with Varithena™, a healthcare professional will watch you for signs of an allergic reaction for at least 10 minutes.

• Damage to skin and tissue

Varithena™ should only be injected into veins. If it is injected into arteries or outside of the vein it can cause permanent injury to the skin or tissue. If this happens, urgent care is required. The damage may be worse if you already have artery disease.

• Blood clots – Deep vein thrombosis

Varithena™ can cause blood clots in the deep veins. Your healthcare professional will monitor you for signs of deep vein thrombosis, typically pain, swelling and blueness of the treated leg. If these symptoms develop after your treatment, see your doctor immediately.

Patients with the following have an increased risk of having a blood clot: difficulty walking, obesity, history of bloots clots in the deep veins of the leg or in the lung, surgery in the last 3 months, long stay in the hospital, cancer, taking oral birth control or hormone replacement therapy, or smoking.

• Mini-strokes

If you know you have a hole in your heart, called a patent foramen ovale (PFO; a common birth defect of the heart that usually causes no problem) you are at greater risk and you should tell your doctor so he can carefully consider if Varithena™ is right for you.

What is Varithena™ used for?

Varithena™ (polidocanol injectable foam) is for the treatment of problems with the great saphenous vein and other saphenous veins and varicose veins of the great saphenous vein system. It is for the treatment of veins above and below the knee. It is only for use in adults with significant venous reflux that was diagnosed by a duplex ultrasound.

How does Varithena™ work?

Varithena will only be administered by a trained doctor. Varithena™ is injected directly into the failed veins and varicose veins. It pushes the blood out of the vein and the active ingredient (polidocanol) irritates the lining of the vein. This causes the vein to go into spasm destroying the lining of the vein, which is then closed. Over several months the vein is slowly resorbed by the body and eventually turns into a thin string of scar tissue.

What are the ingredients in Varithena™?

• Medicinal ingredients: The active product in Varithena™ is polidocanol, although carbon dioxide and oxygen are also required in order to generate the foam.
• Non-medicinal ingredients: ethanol, disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, and water for injection.

Do not use Varithena™ if you:

• Are allergic to polidocanol or any other ingredient in Varithena
• Have a blood clot in your superficial or deep veins (DVT) or have a recent clot in your lung (pulmonary embolism)
• Have blood clotting problems (thrombophilia)

• Are pregnant

To help avoid side effects and ensure proper use, talk to your healthcare professional before you use Varithena™. Talk about any health condition or problems you may have, including if you:

• Had a stroke or mini-stroke (transient ischemic attack)
• Have blood pressure that is not controlled by your medications
• Have heart failure
• Have a hole in your heart, called patent foramen ovale (PFO; a common birth defect of the heart that does not usually cause a problem)
• Are pregnant or trying to become pregnant or are nursing
• Have problems with your liver or kidneys
• Have arterial disease (a disease of the blood vessels)
• Have chest pain or previous heart attack, or other heart disease,
• Can’t walk well or for long
• Ever had a blood clot in your veins or lungs
• Had major surgery in the past 3 months
• Recently had a long hospital stay

Varithena™ is not recommended for children and adolescents under 18 years of age. Other warnings you should know about:

Some people have pain after treatment with Varithena. This pain could make it hard to use your legs, drive or operate machines. Talk to your healthcare professional about the activities you will be able to do after you are treated with Varithena. Tell your healthcare professional about how your leg feels after it is treated with Varithena.

Tell your healthcare professional about all the medicines you take, including any drugs, vitamins, minerals, natural supplements or alternative medicines.

There are no known relevant interactions with Varithena™.

How to use Varithena™:

• Varithena™ will be injected directly into the affected veins of your leg by a trained healthcare professional. A local anesthetic to numb the pain in your leg may be used.
• The procedure will be controlled using ultrasound scanning
• You may require several injections during one treatment session, and may require several treatment sessions to completely treat all veins. Each treatment session will be separated from the next by at least 5 days.
• After treatment, bandages and a compression stocking will be applied. These should be worn without taking them off for 48 hours. Then, only the compression stocking should be worn for the next 12 days.
• You should walk for at least 10 minutes each day after treatment.

Usual Dose

• The amount of Varithena™ injected is carefully controlled by the healthcare professional by using ultrasound to see that the foam has filled the veins being treated. When the veins are filled, the treatment is complete. This will depend on the size and extent of your varicose veins.

Overdose:

The amount of Varithena™ administered is adjusted and monitored by the doctor.

If you feel any discomfort during treatment with Varithena™ tell your doctor immediately.

What are possible side effects from using Varithena™?

These are not all the possible side effects that you may feel when using Varithena™. If you experience any side effects not listed here, contact your healthcare professional.

The most common side effects seen with Varithena™ are:

• Pain, bruising, swelling at the site of injection;
• Brown staining of the skin where the vein has been treated (skin discoloration);
• Leg pain, discomfort and/or swelling;
• Blood clot in the treated vein; removal of this clot may be required;
• Headache;
• Chest pain or discomfort;
• Skin irritation, including rash, itching and/or red patches of skin;
• Muscle spasms;
• Sore joints

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

NOTE: Contact your health professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice.

Storage:

Varithena™ is stored by the hospital or clinic where you receive the treatment. The doctors and hospital pharmacists are responsible for this.

If you want more information about Varithena™:

• Talk to your Healthcare Professional
• Find the full Product Monograph that is prepared for Healthcare Professionals and includes this Patient Medication Information by visiting the Health Canada website (http://www.hc-sc.gc.ca). For questions or to report problems please contact BTG Customer Services by calling 1-844-282-1284 or email pharmacovigilance@btgplc.com.

Varithena™ and VVSymQ™ are trademarks of Provensis Ltd, a BTG International group company. BTG and the BTG roundel logo are trademarks of BTG International Ltd.

Last Revised: October 20, 2017

Varithena^™ Delivery System

Instructions for Use

Please read the Product Monograph before using the product.

The Instructions for Use are for the entire Varithena^TM system. There are 2 packaging configurations:

• Option A: Bi-Canister box and Administration Pack (Varithena Transfer Unit, silicone-free syringes, manometer tubing and compression pads).*

• Option B: Convenience box (Bi-Canister Box + 3 Ancillary Packs + 3 Varithena^TM transfer units)*

  *The components in each packaging configuration are to be used only in conjunction with each other for activation of Varithena^TM.

  Administration Packs can be used for either configuration for further treatment sessions.

Important Facts

• Do not shake Varithena^TM canisters.
• A canister of Varithena^TM generates 90mL of foam which, following purging instructions contained in this IFU, is sufficient to yield 45mL of usable foam for injection. The gas mix of the foam is 65:35 O₂:CO₂.
• Always write the activation date and time on the canister and verify the product has not expired prior to use.

• Once the Varithena^TM canister has been activated, the shelf life for the product is thirty (30) days. The activated

  Varithena^TM canister should always be stored with a Varithena^TM transfer unit in place in the upright position at 20-25°C, with excursions permitted between 15 and 30°C

WARNINGS:

• As the foam fills the syringe and before injecting, inspect the syringe full of foam for any visible bubbles. If there are any present, the foam should be emptied into the Varithena^TM transfer unit waste chamber and the syringe refilled.
• A new Varithena^TM transfer unit must be used for each treatment session.
• Use a new sterile syringe after each injection. Only fill a syringe with foam immediately before it is required as the must be used within 75 seconds of generation or discarded and new foam generated, as the foam quality begins to deteriorate. Unpacking Varithena™:

Option A: Bi-Canister Box and Administration Pack

Gather all the items needed for the generation of foam: the Varithena^TM Bi-Canister box (Figure 1a), Administration Pack (including: Varithena^TM transfer unit, silicone-free syringes, manometer tubing, and compression pads) (Figure 1b), and the following items that are not supplied: scissors, pen, sterile alcoholic wipes, timer and gloves (Figure 1c).

Open the Varithena^TM Bi-Canister box and remove the Varithena^TM Bi-Canister pouch. Open the Administration Pack and remove the components. Inspect the pouch and components for damage (do not use product if there are any visible signs of damage to pouch or components).

Unpacking Varithena™:

Option B: Convenience Box (Bi-Canister Box + 3 Ancillary Packs + 3 Varithena^TM transfer units)

Gather all the items needed for the generation of foam: the Varithena^TM Bi-Canister Box (Figure 2a), Ancillary Pack (including silicone-free syringes, manometer tubing, and compression pads (Figure 2b) and Varithena^TM transfer unit (Figure 2c), and the following items that are not supplied: scissors, pen, sterile alcoholic wipes, timer and gloves (Figure 2d).

Open the Varithena^TM Convenience box and remove all the components. Open the Varithena^TM Bi-Canister box and remove the Varithena^TM Bi-Canister pouch. Open an Ancillary Pack and remove the components. Inspect the pouch and components for damage (do not use product if there are any visible signs of damage to pouch or components).

Preparing the Patient

Preparations for treating the patient with Varithena^TM should include the following steps:

• Position the patient comfortably on the treatment table in a supine position with their hip externally rotated to facilitate access to the GSV.
• Use ultrasound to find the best site for venous access.
• Using an aseptic technique, infiltrate the skin over the venous access point with local anesthetic.
• Obtain venous access under ultrasound guidance.
• IV catheters that are 16 to 22 gauge and 40 - to 50 - mm long or micropuncture sets are recommended for venous access.
• Prefill the manometer tube with sterile heparinised normal saline solution and connect to the IV catheter.
• Confirm venous access by aspirating with a syringe, blood should be dark and under low pressure.
• Flush the IV catheter and manometer tube with heparinised normal saline and secure it to the skin with adhesive tape, leave the saline syringe connected.
• With the IV catheter in place and secure, place the patient supine and elevate the leg to approximately 45 degrees.

Preparation of the patient must be completed before generation of the foam.

Varithena^TM Preparation

Open Bi-Canister pouch using a pair of scissors. Place canisters upright on a clean stable surface with the white oxygen canister on top (Figure 3). Discard empty pouch.

Remove the safety clip by lifting one corner of the clip out (Figure 4). Discard the safety clip.

Gas Activation of the Varithena^TM Canister

To begin the gas transfer, twist the canisters together clockwise (Figure 5) until they come to a stop and the small indicators/marks on the collars are aligned (Figure 6). You may hear a bubbling sound.

While the canisters are activating, keep them upright on a clean flat surface for 1 minute. Use a timing device to keep track of the 1 minute time.

Gas Activation of the Varithena^TM Canister

Note: In order to maintain sterility of the Varithena^TM transfer unit, the following steps must be followed. While waiting 1 minute for the gas transfer, open a new Varithena^TM Transfer Unit, blister pack, but leave the Varithena^TM transfer unit in the package (Figure 7).

The manometer tubing should have been previously filled with sterile heparinised normal saline solution.

Gas Activation of the Varithena^TM Canister

After 1 minute,

• Twist the two canisters by turning them in the opposite direction (counter clockwise) as before (Figure 8).
• Pull straight up to separate the oxygen canister from the Varithena^TM canister, as shown (Figure 9). Do not separate canisters until you have a Varithena^TM transfer unit ready to place onto the Varithena^TM canister (As per step 4).
• Put the oxygen canister (with white collar) aside.
• The Varithena^TM canister (with blue collar) should remain on a clean flat surface, in the upright position.

Connecting a new Varithena^TM transfer unit and syringe

Remove the Varithena^TM transfer unit from the blister pack. Make sure not to touch the sterile underside of the Varithena^TM transfer unit, (discard Varithena^TM transfer unit if contaminated).

Immediately place the Varithena^TM transfer unit on top of the blue Varithena^TM canister. Gently rotate the Varithena^TM transfer unit clockwise as indicated (Figure 11) until it drops into the collar threads then twist the Varithena^TM transfer unit (clockwise) until it reaches a stop (Figure 12).

The system is now activated and ready for use.

Connecting a new Varithena^TM transfer unit and syringe

Once all preparations for injection are complete, i.e., cannula in situ, patient’s leg elevated and a good ultrasound view of the saphenofemoral junction (SFJ) obtained, foam may be generated for immediate use.

Open a sterile 10mL silicone-free syringe package and keep it in the package until needed. Remove the syringe from the package, and connect it to the Varithena^TM transfer unit as shown (Figure 13).

Priming a New Syringe

Gently press down the Varithena^TM transfer unit to begin producing foam (Figure 14).

Using continuous pressure, allow the silicone-free syringe to fill between 3mL and 5mL.

Release the pressure on the Varithena^TM transfer unit and leave the syringe connected.

Priming a New Syringe

Push the silicone-free syringe plunger in fully to discard its contents (Figure 15). Do not disconnect the syringe.

Note: The foam will automatically be diverted into the waste chamber within the Varithena^TM transfer unit (Figure 16). This process eliminates the small quantity of air in the syringe and Varithena^TM transfer unit.

Generation of Foam

Foam Generation: The technique to produce usable foam requires a single purge cycle before filling the syringe, a process that takes less than 1 second.

While holding the silicone-free syringe plunger in place, gently press down on the Varithena^TM transfer unit to begin the purge cycle (Figure 17).

Visually inspect the flowing foam inside the Varithena^TM transfer unit to make sure the visible air bubbles have been expelled (less than 1 second) before releasing the syringe plunger and allowing it to fill to the desired volume (Figure 18).

Draw up to 5mL of foam into the syringe.

Important Note: Foam must be generated by pushing down on the Varithena^TM transfer unit continuously without pulling back on the plunger of the syringe (aspirating).

Inspecting and Injecting Foam

After the silicone-free syringe has filled to the desired volume, wait 10 seconds to allow the pressure to equalize before removing the syringe from the Varithena^TM transfer unit (Figure 19).

WARNING: As the foam fills the syringe and before injecting, inspecting the syringe full of foam for any visible bubbles

(easily seen with the unaided eye at arm’s length). If there are any present, the foam should be emptied into the Varithena^TM transfer unit waste chamber and the syringe refilled.

Remove the syringe from the Varithena^TM transfer unit and inspect it for visible bubbles (Figure 20). If no visible bubbles are present then the foam is ready for use.

Foam must be used within 75 seconds of generation or discarded and new foam generated, as the foam quality begins to deteriorate.

WARNING: The total amount of foam injected in any one treatment session must not exceed 15mL, comprised of individual injections of up to 5mL each.

After each treatment session, mark-off on the canister label the number of aliquots of up to 5mL of usable foam drawn from the canister per step 11 (Figure 21).

Connect a syringe of freshly generated foam to the manometer tubing, which is already connected to the cannula, in preparation for the initial injection.

The manometer tubing should have been previously filled with sterile heparinised normal saline solution

Inspecting and Injecting Foam

Inject the foam at approximately 0.5mL to 1.0mL per second through the manometer tubing. Five (5) mLs of foam should be injected in approximately 10 seconds. Always inspect the foam as it passes through the manometer tubing for visible bubbles (Figure 22). If any visible bubbles are seen (easily seen with the unaided eye at arm's length) they should be aspirated back into the silicone-free syringe and the syringe contents discarded back into the Varithena^TM transfer unit waste chamber, and a fresh syringe of foam generated.

Notes: Use a new sterile syringe after each injection.

WARNING: The total amount of foam injected in any one treatment session must not exceed

15mL, comprised of individual injections of up to 5mL each

Do not remove Varithena^TM transfer unit if the Varithena^TM canister is to be stored (see Storage)

Compression Pads

Once treatment is complete, the Compression Pads should be used:

The objective of the pads is to focus the compression forces on the treated vein to keep them as free from blood as possible, thus minimizing retained thrombus.

The compression pads supplied should be placed along the course of the treated trunk vein in the thigh, and over raised treated varicose veins above and below the knee. The pads may be shaped to follow the course of the veins. The pads should be placed outside the first layer of limited stretch bandage and held in place by a second layer of bandage.

The appropriate length compression stocking is then applied.

Replacing the Varithena^TM transfer unit

Important Note: Do not replace the Varithena^TM transfer unit if the canister is to be stored for future use. The activated Varithena^TM canister should always be stored with a Varithena^TM transfer unit in place in the upright position at controlled room temperature. Replace the Varithena^TM transfer unit just prior to the next treatment session.

While holding the Varithena^TM canister, twist the Varithena^TM

transfer unit counter clockwise then pull up to separate from

the canister (Figure 23).

Discard the old Varithena^TM transfer unit and open a new Varithena^TM transfer unit.

Make sure not to touch the sterile underside of the Varithena^TM transfer unit.

Replacing the Varithena^TM transfer unit

Swab the uncovered shuttle of the canister with a fresh sterile alcohol wipe (Figure 24) and immediately place the Varithena^TM transfer unit on top of the Varithena^TM canister.

Gently rotate the Varithena^TM transfer unit clockwise until it drops into the collar threads (Figure 25), then twist the

Varithena^TM transfer unit (clockwise) until it reaches a stop

(Figure 26).

The Varithena^TM device now ready for use for a new treatment session, following the instructions in Steps 7 to 15.

Storage and Disposal

Note: Once activated, the canister of Varithena should be stored at room temperature in the upright position, and used within 30 days.

The activated Varithena^TM canister should always be stored with a Varithena^TM transfer unit in place in the upright position at controlled room temperature (20-25^oC).Excursions permitted 15- 30^oC.

Do not refrigerate or freeze

Always write the activation date and time on the canister and verify the product has not expired prior to use.

Dispose of Varithena^TM and oxygen canisters following local and national regulations for aerosol disposal.

The Varithena^TM transfer unit can be disposed of as non-toxic non-clinical waste.

Net Contents: 18ml

One canister of Varithena^TM contains:

180mg Polidocanol, Ethanol 756mg (96%), disodium hydrogen phosphate dihydrate 43.2mg, potassium dihydrogen phosphate 15.3mg, water for injection.

One canister of Varithena^TM generates 90mL of foam which, following purging instructions contained in this IFU, is sufficient to yield 45mL of usable foam for injection.

The gas mix of the foam is 65:35 O₂:CO₂.

Manufactured for Provensis Ltd by:

Biocompatibles UK Ltd

Chapman House, Weydon Lane, Farnham, Surrey, UK , GU9 8QL

Varithena™ is a trademark of Provensis Ltd

BTG and the BTG roundel logo are registered trademarks of BTG International Ltd

Provensis Ltd, and Biocompatibles UK Ltd, are BTG International group companies