SUMMARY CMI

UVADEX^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using UVADEX?

UVADEX contains the active ingredient methoxsalen. UVADEX is used to treat chronic graft versus host disease (cGVHD) and cutaneous T-cell lymphoma (CTCL).

For more information, see Section 1. Why am I using UVADEX? in the full CMI.

2. What should I know before I use UVADEX?

Do not use if you have ever had an allergic reaction to UVADEX or any of the ingredients listed at the end of the CMI.

You have a condition which makes you unable to tolerate removal of large quantities of blood, such as heart disease or severe anaemia.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use UVADEX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with UVADEX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use UVADEX?

• UVADEX is administered by a specialist doctor in a hospital in a procedure known as photopheresis.
• Your doctor will administer UVADEX at the dose and duration of treatment required for your condition.

More instructions can be found in Section 4. How do I use UVADEX? in the full CMI.

5. What should I know while using UVADEX?

For more information, see Section 5. What should I know while using UVADEX? in the full CMI.

6. Are there any side effects?

Patients treated for cGVHD have experienced diarrhoea, low platelet count, nausea, headache, and high blood pressure. Other side effects that were reported from patients treated with UVADEX include anaemia, worsening of congestive heart failure, severe infection (sepsis), heart valve infection or inflammation, allergic reactions and vomiting.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

UVADEX^®

Active ingredient(s): methoxsalen

Consumer Medicine Information (CMI)

This leaflet provides important information about using UVADEX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using UVADEX.

Where to find information in this leaflet:

1. Why am I using UVADEX?
2. What should I know before I use UVADEX?
3. What if I am taking other medicines?
4. How do I use UVADEX?
5. What should I know while using UVADEX?
6. Are there any side effects?
7. Product details

1. Why am I using UVADEX?

The active ingredient in UVADEX is methoxsalen. This is a product that alters the response of the body to light which becomes active when it is exposed to UV radiation.

UVADEX is used to treat:

1) Chronic Graft versus Host Disease (cGVHD) is a common and sometimes serious side effect of a blood stem cell transplant. GVHD happens when the cells from your donor (the graft) see your body's cells (the host) as different and attack them, leading to complications involving the skin and other organs of the body.

UVADEX is used in combination with the THERAKOS^® CELLEX^® Photopheresis System to treat chronic GVHD that is no longer responding to steroid treatment.

2) Cutaneous T-cell lymphoma (CTCL) is a blood disorder causing abnormal growths affecting the skin. UVADEX is used in combination with the THERAKOS CELLEX Photopheresis System to alleviate the skin symptoms of CTCL, when other treatments have not been effective.

The THERAKOS CELLEX Photopheresis System provides the UV light necessary to activate methoxsalen which then destroys diseased white blood cells.

2. What should I know before I use UVADEX?

Warnings

Do not use UVADEX if:

• You have had an allergic reaction to methoxsalen, another psoralen compound, or any of the other ingredients.
• You have skin cancer (melanoma, basal cell or squamous cell cancer).
• You have any disease which involves sensitivity to light such as porphyria, systemic lupus erythematosus or albinism (a condition where the pigment in your skin is reduced).
• Your spleen has been removed.
• You have a blood clotting disorder or an increased white blood cell count (greater than 25,000 per mm³).
• You are breast feeding.
• You have a condition which makes you unable to tolerate removal of large quantities of blood, such as heart disease or severe anaemia.
• You have had the lens removed from either of your eyes.

Check with your doctor if you:

• You have epilepsy and are being treated with phenytoin (this may cause UVADEX treatment to be ineffective).
• You have liver or kidney problems.
• You are taking tolbutamide for diabetes (this may cause increased photosensitivity).
• You have sunbathed recently before treatment.
• You are taking any other medicine which causes sensitivity to light.
• There is any possibility of you becoming pregnant.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

You should let your doctor know if there is a chance you are or may be pregnant or intend to become pregnant.

You should not be treated with UVADEX if you are breast feeding.

Use in children

UVADEX is not recommended for use in children.

Use in the elderly

There is no evidence of a requirement for reduction in frequency or duration of treatment with UVADEX in elderly patients.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with UVADEX and affect how it works.

Effects of UVADEX on other medicines

Some medications may interfere with UVADEX, because they are inactivated by the same mechanism as UVADEX, or because they bind to the same body structures as UVADEX.

Caffeine may not be eliminated from the body as quickly as normal while UVADEX is used. The pain reduction of paracetamol may be reduced while UVADEX is given. The concentration of other medicines may be increased and may lead to side effects from these medicines (e.g. dicoumarol, promethazine, tolbutamide and warfarin.

Medicines that may reduce the effect of UVADEX include:

• phenytoin used to treat epilepsy

Medicines that may increase your sensitivity to light after using UVADEX

• Special care should be exercised if you are receiving concomitant therapy (either topically or systemically) with known photosensitising agents.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect UVADEX.

4. How do I use UVADEX?

How much to use

This medicine is always administered by a specialist doctor who can explain exactly what is happening. The doctor will decide how many treatment sessions you need.

When to use UVADEX

cGVHD

Most patients with chronic GVHD may have 3 treatments in the first week, then 2 treatments per week for at least 12 weeks.

CTCL

Most patients with CTCL have treatment on two successive days once a month for six months. After four months this may be increased to two successive days twice a month if the doctor thinks it is necessary. You should not have more than 20 photopheresis sessions in 6 months.

How UVADEX is used

A professional specifically trained in the use of photopheresis will place a needle in your arm so that blood can flow into a specially designed instrument (the THERAKOS CELLEX Photopheresis System) and be separated into red blood cells, white blood cells and plasma. The red blood cells and most of the plasma are simply transfused back into your circulation during the procedure. The white blood cells and the rest of the plasma are mixed with a calculated dose of UVADEX, exposed to UV light in the instrument, and then reinfused to your body.

The procedure takes up to three hours from the time the needle is inserted until all the components of your blood have been reinfused to your body.

During administration of your treatment, and for 24 hours afterwards, you must wear special wraparound UVA-blocking sunglasses all of the time to avoid the light damaging your eyes by causing cataracts to form.

After receiving your treatment

After receiving your treatment you should avoid sunlight for at least 24 hours because it may damage your skin by causing burning or, in the long term, premature aging or skin cancer. If you must go outside you should cover your skin, use a strong sunscreen and wear sunglasses (see above).

If you are given too much UVADEX

This is very unlikely. However, were you to be given too much you may need to remain in a darkened room for 24 hours or longer as part of your treatment.

If you think that you have been given too much UVADEX, you may need urgent medical attention.

You should immediately:

• phone the Poisons Information Centre (by calling 13 11 26), or
• contact your doctor, or
• go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using UVADEX

Things you should do

• For 24 hours after a treatment, wear wrap-around UVA-blocking sunglasses all the time. If you must go outside, use a strong sunscreen and wear protective clothing that covers your skin when exposed to strong sunlight. Your skin may be more sensitive to sunlight after using UVADEX.
• Both men and women who are being treated with UVADEX should take adequate contraceptive precautions both during and after completion of photopheresis treatment.
• Call your doctor straight away if you:
  - Become pregnant
  - Experience an allergic reaction
  - Experience visual disturbances
  - Experience skin changes (e.g. skin burns)

Remind any doctor, dentist or pharmacist you visit that you are using UVADEX.

Things you should not do

• After receiving your treatment, avoid sunlight for at least 24 hours as your skin may be more sensitive to sunlight and UV light after using UVADEX. Do not go out in strong sunlight or use sunlamps, or other sources of ultraviolet (UV) light.

Driving or using machines

You should not drive or operate machinery immediately following treatment.

Drinking alcohol

Tell your doctor if you drink alcohol.

This product contains 4.1% w/v ethanol. Each 10 mL of UVADEX contains 0.41 g of ethanol. This may be harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease.

Looking after your medicine

UVADEX will be stored in the hospital pharmacy in a safe place out of the reach of children.

It should be stored below 25°C.

UVADEX should not be used after the expiry date on the box.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Serious side effects

The side effects in the following table may have potentially serious outcomes.

The photopheresis procedure may result in mild or moderate lowering of blood pressure, fever or local infection or damage to veins as a result of insertion of the needle. These effects have been reported at an incidence of up to 1 in 10 people.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What UVADEX contains

Do not take this medicine if you are allergic to any of these ingredients.

What UVADEX looks like

UVADEX comes in an amber glass vial with a rubber stopper containing 10 mL of solution.

(Aust R 308832)

Who distributes UVADEX

Ikaria Australia Pty Ltd
Ground Floor, 17 Cotham Road,
Kew, Victoria 3101
Phone: (03) 9851 9100
Website: www.ikariaaust.com

This leaflet was prepared in October 2022.

Published by MIMS December 2022

1 Name of Medicine

Methoxsalen.

2 Qualitative and Quantitative Composition

Uvadex methoxsalen concentrated injection is a sterile, clear, colourless to pale yellow liquid containing 200 microgram of methoxsalen per 10 mL vial, which is equivalent to 20 microgram of methoxsalen per mL. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Uvadex is supplied as a sterile concentrated injection for extracorporeal circulation via photopheresis in single-use amber glass vials. Uvadex is used in combination with the Therakos Cellex Photopheresis System to extracorporeally treat leukocyte enriched buffy coat.

4 Clinical Particulars

4.1 Therapeutic Indications

Uvadex (methoxsalen) is indicated for extracorporeal administration with the Therakos Cellex Photopheresis System for the:
Treatment of steroid-refractory and steroid-intolerant chronic graft versus host disease (cGVHD) in adults following allogeneic HSC transplantation.
Palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that is unresponsive to other forms of treatment.

4.2 Dose and Method of Administration

Do not inject directly into patients. Product is for single use in one patient only. Discard any residue.
Photopheresis treatments should always be performed in locations where standard medical emergency equipment is available. Volume replacement fluids and/or volume expanders should be readily available throughout the procedure. Please refer to the Therakos Cellex Operator's Manual for additional warnings and precautions.
In the photopheresis process, the patient is connected to the Therakos Cellex Photopheresis System via a catheter interface. Red blood cells are separated from the white blood cells and plasma in the centrifuge bowl. The red blood cells and excess plasma are returned to the patient while the buffy coat (leukocyte enriched blood) and some plasma are collected into the photoactivation bag located on the side of the instrument.
During each photopheresis treatment with Uvadex, the dosage of Uvadex is calculated according to the treatment volume (which is displayed on the display panel of the instrument) using the formula:
Treatment volume x 0.017 mL of Uvadex for each treatment.
For example: Treatment volume = 240 mL x 0.017 = 4.1 mL of Uvadex.
The prescribed amount of Uvadex is injected into the photoactivation bag prior to the photoactivation phase. During photoactivation the leukocyte enriched blood is continually circulated through the photoactivation module for the time specified by the device, to a maximum of 90 minutes whilst being exposed to UVA light.
At the end of the photoactivation cycle, the photoactivated cells are then reinfused into the patient; the recommended reinfusion time is 15 to 20 minutes. The complete photopheresis procedure is up to 3 hours in duration.

Chronic graft versus host disease.

Cutaneous T-cell lymphoma.

Skin score determination.

Dosage in special populations.

Instructions for use/ handling.

4.3 Contraindications

History of idiosyncratic or hypersensitivity reaction to methoxsalen, psoralen compounds or any of the excipients of Uvadex.
Co-existing melanoma, basal cell or squamous cell skin carcinoma.
Lactation.
Aphakia.
Contraindications to the photopheresis procedure:
Photosensitive disease.
Inability to tolerate extracorporeal volume loss (e.g. due to severe cardiac disease, severe anaemia, etc.).
White blood cell count greater than 25,000 mm³.
Previous splenectomy.
Coagulation disorders.

4.4 Special Warnings and Precautions for Use

Only physicians who have special competence in the diagnosis and treatment of cGVHD and CTCL who have special training and experience with the Therakos Cellex Photopheresis System should use Uvadex. Psoralen and ultraviolet radiation therapy should be under constant supervision of such a physician. Because of the possibilities of ocular damage, the patient should be fully informed by the physician of the risks inherent in this therapy. Uvadex should only be used ex vivo and administered directly into the photoactivation bag. Visually inspect for haemolysis. In the event of unscheduled damage to the blood during the photopheresis procedure (e.g. > 43°C alarm sounding), the fractionated blood should only be reinfused into the patient if haemolysis has not occurred.

Contraceptive precautions.

Cataractogenicity.

Adverse effects on the skin.

Venous and arterial thromboembolism.

Alcohol content.

Use in hepatic impairment.

Use in renal impairment.

Use in the elderly.

Paediatric use.

Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Although methoxsalen has been shown to be capable of both induction and inhibition of hepatic enzymes, in humans it appears to act primarily as a potent inhibitor of hepatic microsomal oxidative metabolic processes, including, but not limited to, CYP1A2, 2A6 and 2B1. Thus, it is to be expected that interactions will occur between methoxsalen and other medicinal products whose metabolism involves the hepatic cytochrome P450 system. The clearance of caffeine has been shown to be markedly reduced after methoxsalen treatment. Methoxsalen decreases the metabolic activation of paracetamol in animals and humans, probably as a consequence of methoxsalen-associated inhibition of hepatic cytochrome P450 oxidative transformation of paracetamol.
Methoxsalen is metabolically cleared. Therefore, consumption of other P450 substrates and P450 inhibitors may result in an extended half-life of methoxsalen, and consequently lead to prolonged photosensitivity requiring continued precautions against exposure to sunlight beyond 24 hours following photopheresis treatment.
One report describes a patient with psoriasis and epilepsy in whom phenytoin administration induced increased metabolism of methoxsalen leading to low levels of methoxsalen and failure of PUVA therapy. Substitution of valproate for phenytoin resulted in a three to four fold increase in methoxsalen levels to within the putative therapeutic range.
Methoxsalen is normally moderately bound to albumin but can be displaced by a number of medicinal products such as dicoumarol, promethazine and tolbutamide. As a coumarin derivative, it is conceivable that methoxsalen binds to the warfarin site of albumin, which could be of clinical significance when the two medicinal products are co-administered. However, of the medicinal products studied, only tolbutamide at therapeutic concentrations displaces methoxsalen from its binding site to a clinically relevant extent. Concomitant use of methoxsalen and tolbutamide may therefore lead to enhanced photosensitivity.
Special care should be exercised in treating patients who are receiving concomitant therapy (either topically or systemically) with known photosensitising agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

4.7 Effects on Ability to Drive and Use Machines

Patients should not drive or operate machinery immediately following photopheresis because of the possibility of transient cardiovascular instability and the recommendation that following photopheresis patients wear sunglasses. Photopheresis treatment using Uvadex is likely to produce minor or moderate undesirable effects.

4.8 Adverse Effects (Undesirable Effects)

Graft versus host disease.

Cutaneous T-cell lymphoma.

Cardiac disorders.

Gastrointestinal disorders.

Infections.

Procedural complications.

Post-marketing experience.

Reporting suspected adverse effects.

4.9 Overdose

There is no human experience of overdose with Uvadex; animal data suggests a large margin of safety. In the event of methoxsalen overdose, the patient should be kept in a darkened room for at least 24 hours.
If overdose is suspected or an incorrect dose of Uvadex is delivered into the photoactivation bag, immediately terminate treatment.
There is one case of overdosage with oral methoxsalen recorded in the medical literature. A 25-year-old woman ingested a dose equivalent to about 85 mg/kg body weight (i.e. approximately 140 times the therapeutic dose of oral methoxsalen). The major symptoms of intoxication were nausea, vomiting and dizziness. The patient was kept in a darkened room and her cardiovascular function was monitored. She recovered without sequelae and was released from hospital 36 hours after admission.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins.

5.1 Pharmacodynamic Properties

Mechanism of action.

Clinical trials.

Chronic GVHD.

GVHD-SK1.

Dignan 2014.

Gandelman 2018.

Cutaneous T-cell lymphoma.

Sponsor-initiated clinical study.

Published clinical studies.

Australian patient data under the special access scheme.

5.2 Pharmacokinetic Properties

The pharmacokinetics of intravenously administered methoxsalen have been studied in three groups of healthy volunteers who received 5, 10 or 15 mg methoxsalen infused over 60 minutes. The pharmacokinetics of methoxsalen were best described by a three-compartment, mammillary model in which the volumes and clearances were proportional to weight. The mean pharmacokinetic parameters are shown in Table 4.
In a clinical study conducted with Uvadex, methoxsalen concentrations in plasma 30 minutes after reinfusion of the photoactivated cells were less than 10 nanogram/mL in 82% of the 754 samples measured. The mean plasma methoxsalen level was approximately 25 nanogram/mL.

Distribution.

Metabolism.

Excretion.

5.3 Preclinical Safety Data

Preclinical effects were observed only at exposures significantly in excess of the maximum human exposure indicating little relevance to clinical use except as described in other sections (see Section 4.4 Special Warnings and Precautions for Use).
No potential manifestations of toxicity were identified as a result of a four week simulation toxicity study in dogs subjected to extracorporeal photopheresis, at 1-2 J/cm², on a total of eight occasions when Uvadex was added to the buffy coat at concentrations of 100 and 500 nanogram/mL.
The potential for phototoxicity has been extensively studied in animal models. Manifestations of phototoxic responses have been identified in the skin and eye after oral dosing and the liver after intraperitoneal dosing. Studies in humans have shown that phototoxic responses are unlikely to occur unless systemic exposures of at least 30 nanogram/mL are achieved. As plasma methoxsalen concentrations following re-infusion of leukocyte enriched plasma after completion of extracorporeal photopheresis are consistently below the level of detection (10 nanogram/mL), the findings from the animal studies are of limited relevance in the context of the use of Uvadex.

Genotoxicity.

Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Uvadex contains the following excipients: ethanol; propylene glycol; glacial acetic acid; sodium acetate trihydrate; sodium chloride; sodium hydroxide; water for injections. The drug product formulation contains 4.1% w/v ethanol and each 1 mL of Uvadex contains 40.55 mg of ethanol.

6.2 Incompatibilities

Only the photopheresis procedural kits supplied for use with the Therakos Cellex Photopheresis System should be used to administer this medicinal product. In-vitro studies indicate that typical sorption of Uvadex by plastics in the instrument's photopheresis photoactivation circuit during a photopheresis treatment is approximately 30%; however, sorption is significantly reduced once the product is diluted with plasma/buffy coat in clinical practice, resulting in no clinical impact.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Uvadex methoxsalen 200 microgram/10 mL concentrated injection for extracorporeal circulation via photopheresis contains 200 microgram of methoxsalen (or 20 microgram per 1 mL) and is available in single-use, amber glass Type 1 vials in a pack size of 12 x 10 mL vials.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

References

Alfred, A, et al. British Journal of Haematology, 2017; 177(2): 287-310.
Dignan FL., et al. Bone Marrow Transplantation, 2014; 49(5): p. 704-708.
Gandelman JS., et al. Biology of Blood and Marrow Transplantation, 2018; 24(12): 2373-2380.
Gao C., et al. Blood. 2019; 134(16): 1346-1350.
McGirt LY., et al. Photodermatology, Photoimmunology and Photomedicine, 2010; 26(4): 182-91.
Raphael BA, et al. Archives of Dermatology, 2011; 147(12): 1410-1415.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes