Consumer medicine information

Ikervis

Ciclosporin

BRAND INFORMATION

Brand name

Ikervis

Active ingredient

Ciclosporin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ikervis.

SUMMARY CMI

IKERVIS®

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 IKERVIS®?

IKERVIS® contains the active ingredient ciclosporin. IKERVIS® is used to treat severe keratitis in adult patients with dry eye disease which has not improved despite treatment with artificial tears.

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

2. What should I know before I use IKERVIS®?

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

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 IKERVIS®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with IKERVIS® 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 IKERVIS®?

  • The usual dose of IKERVIS® is one drop, once daily, to be applied to the affected eye(s) at bedtime.
  • Follow all directions given to you by your doctor, optometrist or pharmacist carefully. They may differ from the information contained in this leaflet.

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

5. What should I know while using IKERVIS®?

Things you should do
  • Tell your doctor immediately if you become pregnant.
  • Tell any doctor, dentist, optometrist or pharmacist who treat you that you are using IKERVIS®.
  • Tell your doctor immediately if you develop any signs of an allergic reaction after use.
Things you should not do
  • Do not start using any other medicine including any that you can buy without a prescription from your pharmacy, supermarket, health food shop, naturopath or herbalist, without first talking to your doctor or optometrist.
  • Do not stop using this medicine without checking with your doctor or optometrist.
  • Do not give IKERVIS® to anyone else, even if they have the same condition as you.
Driving or using machines
  • Your vision may be blurred immediately after using IKERVIS® eye drops. If this happens, wait until your vision clears before you drive or use machines.
Looking after your medicine
  • Keep the IKERVIS® single-dose containers in the foil pouch until it is time to use them. This helps protect them from light.
  • Keep the pack in a cool dry place where the temperature stays below 30°C.
  • Do not store IKERVIS® or any other medicine in the bathroom or near a sink or stove. Do not leave the pack in a car or on a window sill.

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

6. Are there any side effects?

The most common side effects are eye pain and eye irritation. These side effects are usually temporary and associated with administering the drops to the eye.

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

IKERVIS®

Active ingredient(s): Ciclosporin

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using IKERVIS®?

IKERVIS® contains the active ingredient ciclosporin. Ciclosporin belongs to a group of medicines known as immunosuppressive agents that are used to reduce inflammation.

IKERVIS® is used to treat adults with severe keratitis (inflammation of the cornea, the transparent layer in the front part of the eye) as a result of dry eye disease, which has not improved despite treatment with tear substitutes (artificial tears).

2. What should I know before I use IKERVIS®?

Warnings

Do not use IKERVIS® if:

  • you are allergic to ciclosporin, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you have or have had a cancer in or around your eye
  • you have an eye infection.

Check with your doctor if you:

  • have any other medical conditions, in particular, any conditions which affect your eyes
  • take medicines for any other condition, particularly medicines that belong to a group called steroids or medicines used to treat glaucoma
  • if you have previously had an eye infection caused by the herpes virus that might have damaged the transparent front part of the eye (cornea).

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?

Contact Lenses

Contact lenses can further damage the transparent front part of the eye (cornea). Therefore, you should remove your contact lenses at bedtime before using IKERVIS; you can reinsert them when you wake up.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

IKERVIS® should not be used if you are pregnant or planning to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if IKERVIS® passes into breast milk.

Adolescent and children under 18 years.

IKERVIS® should not be used in children and adolescents under the age of 18 years.

3. What if I am taking other medicines?

Tell your doctor, optometrist 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.

Co-administration of IKERVIS® with eye drops containing corticosteroids could increase the effects of ciclosporin on the immune system. This could increase the risk of side effects.

IKERVIS® eye drops should be used at least 5 minutes after any other eye drops are used.

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

4. How do I use IKERVIS®?

How much to use

  • The usual dose of IKERVIS® is one drop in each affected eye, once daily at bedtime.
  • Follow the instructions provided and use IKERVIS® until your doctor or optometrist tells you to stop.

When to use IKERVIS®

  • IKERVIS® should be used once daily at bedtime.

How to use IKERVIS®

Follow these instructions carefully and ask your doctor or pharmacist if there is anything you do not understand.

  • Wash your hands.
  • If you wear contact lenses, take them out before using the drops; you can reinsert them when you wake up.
  • Open one of the foil pouches. Each pouch contains 5 single-use containers (ampoules).
  • Take one single-use container from the foil pouch.
  • Gently shake the container prior to use.
  • Twist off the cap.

  • Pull down your lower eyelid.

  • Tilt your head back and look up at the ceiling.
  • Gently squeeze one drop of the medicine onto your eye. Make sure you do not touch your eye with the tip of the single-use container.
  • Blink a few times so that the medicine covers your eye.
  • After using IKERVIS®, press a finger into the corner of your eye by the nose and gently close your eyelids for 2 minutes. This helps to stop IKERVIS® getting into the rest of the body.

  • If you use drops in both eyes, repeat the steps for your other eye.
  • Discard the single-use container as soon as you have used it, even if there is still some liquid left in it.
  • The remaining single-use containers should be kept in the foil pouch.

If a drop misses your eye, try again.

If you use more IKERVIS® than you should, rinse your eye with water. Do not put in any more drops until it is time for your next regular dose.

If you forget to use IKERVIS®

IKERVIS® should be used regularly at approximately the same time each day. If you forget to use IKERVIS® at bedtime, wait until the next dose as planned. Do not use a double dose to make up for the forgotten dose. Do not use more than one drop each day in the affected eye(s).

If you are not sure what to do, ask your doctor, optometrist or pharmacist.

If you stop using IKERVIS® without speaking to your doctor or optometrist, the inflammation of the transparent front part of your eye (known as keratitis) may not be controlled and could lead to impaired vision.

If you use too much IKERVIS®

If you think that you have used too much IKERVIS®, immediately rinse your eye(s) with water.

If you think that you or anyone else may have swallowed any or all of the IKERVIS® eye drops, 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 IKERVIS®?

Things you should do

  • Tell your doctor immediately if you become pregnant.

Remind any doctor, dentist, pharmacist or optometrist you visit that you are using IKERVIS®.

Things you should not do

  • Do not stop using this medicine without checking with your doctor or optometrist.
  • Do not give IKERVIS® to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how IKERVIS® affects you.

Your vision may be blurred immediately after using IKERVIS® eye drops. If this happens, wait until your vision clears before you drive or use machines.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

  • Keep the IKERVIS® single-dose containers in the foil pouch until it is time to use them. This is important to protect the product from light and to avoid evaporation.
  • Keep the pack in a cool dry place where the temperature stays below 25°C.
  • Do not freeze.

Store the pack in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep the pack where young children cannot reach it.

When to discard your medicine

Discard any opened individual single-dose container with any remaining emulsion immediately after use.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Eyes - related:
  • Pain or irritation when you put the drops into your eye
  • Redness of your eye
  • Redness or swelling of the eyelid or conjunctiva (tissue inside the eyelids)
  • Watery eyes
  • Blurred vision
  • Discomfort or itching in or around the eye, including the feeling that there is something in the eye
  • Cyst in the eyelid
Body Related
  • Headache
Speak to your doctor or optometrist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Eyes - related:
  • New eye pain
  • Changes in colour of the iris (coloured part of the eye) or cornea (transparent front part of the eye)
  • Increased eye discharge
  • Abrasion to the outer layer of the eye
  • Bacterial infection
  • Deposits in the eye
  • Immune response or scarring in the cornea
  • Painful rash around the eye
Body - related:
  • Swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • Asthma, wheezing, breathlessness, sudden or severe itching, skin rash, hives

These side effects may be signs of an allergic reaction.

Call your doctor or optometrist straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor, optometrist 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 IKERVIS® contains

Active ingredient
(main ingredient)		Ciclosporin.
Other ingredients
(inactive ingredients)		Medium chain triglycerides
Cetalkonium chloride
Glycerol
Poloxamer
Sodium hydroxide
Water for injections

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

IKERVIS® does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

What IKERVIS® looks like

IKERVIS® is a milky white eye drop emulsion.

It is supplied in single-dose containers made of a low-density polyethylene (LDPE).

Each single-dose container contains 0.3 mL of the eye drop emulsion.

A strip of 5 single-dose containers is wrapped in a sealed aluminium foil pouch.

Each box of IKERVIS® contains 30 single-dose containers (6 foil pouches each containing a strip of 5 single-dose containers).

Aust R 319502.

Who distributes IKERVIS®

Seqirus Pty Ltd
ABN 26 160 735 035
63 Poplar Road,
Parkville, VIC, 3052
Australia
Telephone: 1800 642 865
www.seqirus.com.au

IKERVIS is a registered trademark of Santen SAS.

This leaflet was prepared in November 2023.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Ikervis

Active ingredient

Ciclosporin

Schedule

S4

 

1 Name of Medicine

Ciclosporin.

2 Qualitative and Quantitative Composition

One mL of Ikervis emulsion contains 1 mg (0.1%) of ciclosporin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Eye drops, emulsion.
Milky white liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of severe keratitis in adult patients with dry eye disease which has not improved despite treatment with tear substitutes.

4.2 Dose and Method of Administration

Treatment should be initiated by an ophthalmologist or appropriately qualified healthcare professional with expertise in the diagnosis, assessment and treatment of keratitis associated with dry eye disease (see Section 4.4 Special Warnings and Precautions for Use).

Dosage.

Adults.

The recommended dose is one drop of Ikervis once daily to be applied to the affected eye(s) at bedtime.
Response to treatment should be reassessed at least every 6 months.
If a dose is missed, treatment should be continued on the next day as normal. Patients should be advised not to instil more than one drop in the affected eye(s).

Paediatric patients.

Ikervis has not been studied in patients below 18 years of age.

Elderly patients.

The elderly population has been studied in clinical studies. No dosage adjustment is required.

Renal impairment.

The effect of Ikervis has not been studied in patients with renal impairment. However, no special considerations are needed in these populations.

Hepatic impairment.

The effect of Ikervis has not been studied in patients with hepatic impairment. However, no special considerations are needed in these populations.

Method of administration.

Ocular use.

Precautions to be taken before administering the medicinal product.

Patients should be instructed to first wash their hands.
Prior to administration, the single-dose container should be gently shaken.
For single use in one patient only. Each single-dose container is sufficient to treat both eyes. Any unused emulsion should be discarded immediately.
Patients should be instructed to use nasolacrimal occlusion and to close the eyelids for 2 minutes after instillation, to reduce the systemic absorption. This may result in a decrease in systemic undesirable effects and an increase in local activity (see Section 4.4 Special Warnings and Precautions for Use).
If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart. Ikervis should be administered last (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.
Ocular or peri-ocular malignancies or premalignant conditions.
Active or suspected ocular or peri-ocular infection. Treatment with Ikervis should not be initiated or continued until all signs of infection have cleared.

4.4 Special Warnings and Precautions for Use

A comprehensive eye examination should be performed to determine the aetiology of symptoms. Any reversible underlying conditions, not associated with dry eye disease, should be treated prior to initiating treatment with Ikervis.
Ikervis has not been studied in patients with a history of ocular herpes and should therefore be used with caution in such patients.

Contact lenses.

Patients wearing contact lenses have not been studied. Careful monitoring of patients with severe keratitis is recommended. Contact lenses should be removed before instillation of the eye drops at bedtime and may be reinserted at wake-up time.

Concomitant therapy.

There is limited experience with Ikervis in the treatment of patients with glaucoma. Caution should be exercised when treating these patients concomitantly with Ikervis, especially with beta-blockers, which are known to decrease tear secretion.
Co-administration of Ikervis with eye drops containing corticosteroids may potentiate the effects of Ikervis on the immune system. Therefore, caution should be exercised when corticosteroids are administered concomitantly with Ikervis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Effects on the immune system.

Ophthalmic medicinal products, which affect the immune system, including ciclosporin, may affect host defences against local infections and malignancies. Therefore, regular examination of the eye(s) is recommended, e.g. at least every 6 months.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Ikervis.

Combination with other medicinal products that affect the immune system.

Co-administration of Ikervis with eye drops containing corticosteroids could potentiate the effects of ciclosporin on the immune system (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There is no data on the effects of Ikervis on human fertility.
Male and female fertility were unaffected by ciclosporin in rats at oral doses up to 15 mg/kg/day (more than 2000 times higher than the maximum recommended human ophthalmic dose, based on body surface area-adjusted doses for a 50 kg subject).

Women of childbearing potential/contraception in females.

Ikervis is not recommended in women of childbearing potential not using effective contraception.
(Category C)
There are no data from the use of Ikervis in pregnant women.
Ciclosporin has been shown to be embryo- and fetotoxic in rats and rabbits at doses toxic to dams (rat at 30 mg/kg per day and rabbit at 100 mg/kg per day orally). Toxicity was indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardations. In the well-tolerated dose range (rats up to 17 mg/kg per day and rabbits up to 30 mg/kg per day orally, more than 2500 times higher than the maximum recommended human ophthalmic dose, based on body surface area-adjusted doses for a 50 kg subject) ciclosporin did not demonstrate embryolethal or teratogenic effects.
In two published research studies, rabbits exposed to ciclosporin in utero (10 mg/kg/day subcutaneously, more than 3000 times higher than the maximum recommended human ophthalmic dose, based on body surface area-adjusted doses for a 50 kg subject) had reduced numbers of nephrons. These rabbits exhibited renal hypertrophy, systemic hypertension and progressive renal insufficiency when examined between 11 and 35 weeks of age in one study.
The clinical relevance of these findings to the ocular use of Ikervis is unknown as the systemic absorption of ciclosporin following administration of Ikervis was found to be either below the limit of detection or, when detected, considered to be negligible (see Section 5.2 Pharmacokinetic Properties).
However, Ikervis is not recommended during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.
 Following oral administration, ciclosporin is excreted in breast milk. There is insufficient information on the effects of Ikervis on breastfed infants. However, at therapeutic doses of ciclosporin in eye drops, it is unlikely that sufficient amounts would be present in breast milk. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from Ikervis therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Ikervis has moderate influence on the ability to drive and use machines.
This medicinal product may induce temporary blurred vision or other visual disturbances which may affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be advised not to drive or use machines until their vision has cleared.

4.8 Adverse Effects (Undesirable Effects)

In five clinical studies including 532 patients who received Ikervis and 398 who received Ikervis vehicle (control), Ikervis was administered at least once a day in both eyes, for up to one year. The most common adverse reactions were eye pain (19.0%), eye irritation (17.5%), ocular hyperaemia (5.5%), lacrimation increased (4.9%) and eyelid erythema (1.7%) which are usually transitory and occurred during instillation. These adverse reactions are consistent with those that have been reported during post-marketing experience.
The majority of adverse reactions reported in clinical studies with the use of Ikervis were ocular and mild to moderate in severity.

Tabulated list of adverse reactions.

The adverse reactions listed below were observed in clinical studies or during post-marketing experience. They are ranked according to system organ class and classified according to 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 (< 1/10,000), or not known (cannot be estimated from the available data). See Table 1.
The tabulated data on the most frequent adverse events (in particular the ocular AEs) for Ikervis compared to vehicle is presented in Table 2.

Description of selected adverse reactions.

Eye pain.

Eye pain was a frequently reported local adverse reaction associated with the use of Ikervis during clinical trials. It is likely to be attributable to ciclosporin.

Generalised and localised infections.

Patients receiving immunosuppressive therapies, including ciclosporin, are at increased risk of infections. Both generalised and localised infections can occur. Pre-existing infections may also be aggravated (see Section 4.3 Contraindications). Cases of infections have been reported uncommonly in association with the use of Ikervis.
As a precautionary measure, action should be taken to reduce systemic absorption (see Section 4.2 Dose and Method of Administration).

Adverse event reporting.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

A topical overdose is not likely to occur after ocular administration. If overdose with Ikervis occurs, treatment should be symptomatic and supportive.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ciclosporin is a calcineurin inhibitor immunosuppressant agent when administered systemically. Ciclosporin has been shown to have an anti-inflammatory effect whereby it inhibits the production and/or release of pro-inflammatory cytokines and has been shown to up-regulate the release of anti-inflammatory cytokines. In patients with dry eye disease, topical administration of ciclosporin is believed to exert an immunomodulatory effect, although its exact mechanism of action in dry eye disease is not known.

Clinical trials.

The efficacy and safety of Ikervis were evaluated in two pivotal, Phase III, randomised, double-masked, vehicle-controlled clinical studies in adult dry eye disease (DED, keratoconjunctivitis sicca) patients with keratitis. Each study included assessment of both an objective sign (keratitis) and subjective symptoms of the disease as part of the primary efficacy endpoint.

SICCANOVE study.

The first pivotal study, the SICCANOVE study, randomised 492 DED patients with moderate to severe keratitis (defined as a corneal fluorescein staining (CFS) score of 2 to 4 as measured on the modified Oxford scale) to receive either Ikervis or vehicle once-daily, at bedtime, for 6 months. The co-primary endpoints of this study were change in CFS score and change in global score of ocular discomfort unrelated to study medication instillation, both measured at Month 6. The mean improvement in CFS scores was statistically significantly greater with Ikervis than vehicle (mean change from baseline in CFS -1.05 with Ikervis and -0.82 with vehicle, p=0.009). The mean change from baseline in ocular discomfort score (assessed using a visual analogue scale) showed no significant difference between Ikervis and vehicle (-12.82 vs -11.21 respectively, p=0.808).
In patients with a baseline CFS score of 4 (n = 85) (severe disease), the percentage of co-responders with improvement in both sign and symptoms (defined as patients with at least 2 grades improvement in CFS on the modified Oxford scale and at least 30% improvement in Ocular Surface Disease Index (OSDI)) was 32.56% vs 7.14% at Month 6 for the Ikervis and vehicle groups respectively (p=0.003, post-hoc analysis).

SANSIKA study.

The second pivotal study, the SANSIKA study, randomised 246 dry eye disease patients with severe keratitis (defined as a CFS score of 4 on the modified Oxford scale) to receive one drop of Ikervis or vehicle once-daily, at bedtime, for 6 months. The average duration of severe DED prior to study start was 8 - 9 years. Following completion of the initial 6 Month double-masked phase of the study, patients in the vehicle group were switched to Ikervis for a further 6 month open label follow-up.
The primary efficacy outcome was a composite endpoint consisting of the proportion of patients achieving both a two-grade or greater improvement in keratitis (measured by CFS) and a 30% improvement in symptoms (measured by the OSDI) by Month 6. At the end of the initial 6 month treatment period, the proportion of responders in the Ikervis group was 28.6%, compared with 23.1% in the vehicle group. The difference was not statistically significant (p = 0.326).
A significantly greater improvement in CFS score was observed at Month 6 in the Ikervis group compared with vehicle. The adjusted mean difference in CFS scores between the two groups was -0.35 (-1.76 vs -1.42 for the Ikervis and vehicle groups respectively; p = 0.037). An improvement in favour of Ikervis was also observed at Month 3 (p = 0.024).
With regard to improvement in symptoms, there was no significant difference between Ikervis and vehicle groups at Month 6 as measured using the OSDI (-13.6 vs -14.1 respectively. The improvement from baseline to Month 6 for both groups exceeded the minimal clinically important difference (MCID) for OSDI for severe OSDI symptoms at baseline.
The proportion of Ikervis-treated patients with at least a 3-grade improvement in CFS score at Month 6 was 31.2%, compared with 13.2% of vehicle treated subjects (post-hoc analysis). Patients who recorded a CFS score of 1 or lower after 6 months treatment achieved almost complete or complete corneal clearing respectively.
A reduction in the ocular surface inflammation assessed with Human Leukocyte Antigen-DR (HLA-DR) expression, was observed at Month 6 in favour of Ikervis.

Post-SANSIKA study.

Following completion of the SANSIKA study (12 month study), patients were asked to enter the Post-SANSIKA study. This study was an open-label, non-randomised, one-arm, 24-month extension of the SANSIKA Study. In this study patients received either treatment with Ikervis or no treatment depending on their CFS score (patients received Ikervis when there was a worsening of keratitis).
This study was designed to monitor the long-term efficacy and relapse rates in patients who have previously received Ikervis.
The primary objective of the study was to assess the duration of improvement following discontinuation of treatment with Ikervis. Treatment was discontinued once a patient's CFS score (on the modified Oxford scale) had improved by at least 2 grades with respect to the SANSIKA study baseline score of CFS grade 4.
67 patients were enrolled (37.9% of the 177 patients who completed the SANSIKA study). After the 24-month period, 61.3% of 62 patients included in the primary efficacy population did not experience a relapse based on CFS scores. Recurrence of severe keratitis was observed in 35% and 48% of patients who had received Ikervis for 12 months or 6 months respectively in the SANSIKA study.

5.2 Pharmacokinetic Properties

Formal pharmacokinetic studies have not been conducted in humans with Ikervis.

Absorption.

Blood concentrations of Ikervis were measured using a specific high-pressure liquid chromatography-mass spectrometry assay. In 374 patients from the two efficacy studies, plasma concentrations of ciclosporin were measured before administration and after 6 months (SICCANOVE study and SANSIKA study) and 12 months of treatment (SANSIKA study). After 6 months of ocular instillation of Ikervis once per day, 327 patients had values below the lower limit of detection (0.050 nanogram/mL) and 35 patients were below the lower limit of quantification (0.100 nanogram/mL). Measurable values not exceeding 0.206 nanogram/mL were measured in eight patients; values considered to be negligible. Three patients had values above the upper limit of quantification (5 nanogram/mL) however they were already taking oral ciclosporin at a stable dose, which was allowed by the studies' protocol. After 12 months of treatment, values were below the lower limit of detection for 56 patients and below the lower limit of quantification in 19 patients. Seven patients had measurable values (from 0.105 to 1.27 nanogram/mL), all considered to be negligible values. Two patients had values above the upper limit of quantification, however they were also on oral ciclosporin at a stable dose since their inclusion in the study.

5.3 Preclinical Safety Data

Genotoxicity.

Ciclosporin was not genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. An in vitro sister chromatid exchange (SCE) assay using human lymphocytes gave indications of a positive effect for ciclosporin at high concentrations.

Carcinogenicity.

Systemic carcinogenicity studies have been carried out in rats and mice. In a 78-week mouse study, at oral doses of 1, 4 and 16 mg/kg per day (more than 1200 times higher than the maximum recommended human ophthalmic dose, based on body surface area-adjusted doses for a 50 kg subject), a trend towards increased incidences of lymphomas at the highest dose studied was observed. In another study with ARK mice treated with higher ciclosporin doses in the diet, ciclosporin accelerated the development of lymphomas.
In a 24-month rat study, conducted with oral doses of 0.5, 2 and 8 mg/kg per day (up to at least 1200 times the maximum recommended human ophthalmic dose, based on body surface area-adjusted doses for a 50 kg subject), no significant increase in tumour incidence was reported, though the study had limited sensitivity. Ciclosporin enhanced the development of lymphomas induced in two strains of male mice by single whole body irradiation or N-methyl-n-nitrosurea.

6 Pharmaceutical Particulars

6.1 List of Excipients

Medium chain triglycerides, cetalkonium chloride, glycerol, tyloxapol, poloxamer, sodium hydroxide (for pH adjustment), water for injections.

6.2 Incompatibilities

Not applicable (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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. Do not freeze. Protect from light.
After opening of the aluminium pouches, the single-dose containers should be kept in the pouches in order to protect from light and avoid evaporation. Any opened individual single-dose container with any remaining emulsion should be discarded immediately after use.

6.5 Nature and Contents of Container

Ikervis is supplied in 0.3 mL single-dose, low-density polyethylene (LDPE) ampoules presented in a sealed laminate aluminium pouch.
One pouch contains five single-dose ampoules. Ikervis is for single use in one patient only. Discard any residue after opening.
Pack sizes: 30 single-use ampoules (5 connected ampoules per pouch, 6 pouches per carton).

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.

The chemical structure of ciclosporin:

CAS number.

59865-13-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (S4): Prescription Only Medicine.

Summary Table of Changes