ROCLANDA 50 MICROGRAMS / ML + 200 MICROGRAMS / ML EYE DROPS SOLUTION - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Roclanda 50 micrograms/ml + 200 micrograms/ml eye drops, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 50 micrograms latanoprost and 200 micrograms netarsudil (as mesylate).

Excipient(s) with known effect

Each ml of solution contains 200 micrograms benzalkonium chloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Eye drops, solution.

Clear, colourless solution, pH 5 (approximately).

Osmolality: 280 mOsm/Kg.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Roclanda is indicated for the reduction of elevated intraocular pressure (IOP) in adult patients with primary open-angle glaucoma or ocular hypertension for whom monotherapy with a prostaglandin or netarsudil provides insufficient IOP reduction.

4.2 Posology and method of administration

Treatment with Roclanda should only be initiated by an ophthalmologist or a healthcare professional qualified in ophthalmology.

Posology

Use in adults, including the elderly

The recommended dosage is one drop in the affected eye(s) once daily in the evening. Patients should not instill more than one drop in the affected eye(s) each day.

If one dose is missed, treatment should continue with the next dose in the evening.

Paediatric population

The safety and efficacy of Roclanda in children below the age of 18 years have not been established.

No data are available.

Method of administration

For ocular use.

Data on potential interactions specific to latanoprost + netarsudil are described in section 4.5. If latanoprost + netarsudil is to be used concomitantly with other topical ophthalmic medicinal products, each medicinal product should be administered at least five minutes apart. Due to netarsudil’s va­sodilating properties, other eye drops should be administered before latanoprost + netarsudil. Eye ointments should be administered last.

Contact lenses should be removed prior to instillation of latanoprost + netarsudil and may be reinserted 15 minutes following its administration (see section 4.4).

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute. This should be performed immediately following the instillation of each drop.

The tip of the dispensing container should avoid contacting the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Iris pigmentation

Latanoprost may gradually change eye colour by increasing the amount of brown pigment in the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia.

Increased iris pigmentation has not been shown to have any negative clinical sequelae and treatment with medicinal products containing latanoprost can be continued if iris pigmentation ensues. However, patients should be monitored regularly and if the clinical situation warrants, treatment with medicinal products containing latanoprost may be discontinued.

Herpetic keratitis condition

Medicinal product(s) containing latanoprost should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Macular oedema risk

Reports of macular oedema with medicinal products containing latanoprost have occurred mainly in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema (such as diabetic retinopathy and retinal vein occlusion). Medicinal products containing latanoprost should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.

Iritis/uveitis risk

In patients with known predisposing risk factors for iritis/uveitis, medicinal products containing latanoprost can be used with caution.

Asthma exacerbation

There is limited experience of latanoprost use in patients with asthma, but some cases of exacerbation of asthma and/or dyspnoea were reported in post marketing experience. Asthmatic patients should therefore be treated with caution until there is sufficient experience with the combination.

Periorbital skin discolouration

Periorbital skin discolouration has been observed on treatment with medicinal products containing latanoprost, the majority of reports being in Japanese patients. Experience to date shows that periorbital skin discolouration is not permanent and in some cases has reversed while continuing treatment with latanoprost.

Eyelash changes

Treatment with medicinal products containing latanoprost may gradually change eyelashes and vellus hair in the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Benzalkonium chloride content

This medicinal product contains benzalkonium chloride.

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface and is known to discolour soft contact lenses. It should be used with caution in dry eye patients and in patients where the cornea may be compromised.

Patients should be monitored in case of prolonged use.

The efficacy of Roclanda has not been studied beyond 12 months.

4.5 Interaction with other medicinal products and other forms of interaction In vitro interaction studies have shown that precipitation can occur when eye drops containing thimerosal are mixed with latanoprost + netarsudil. Administer other eye drops at least five minutes apart (see section 4.2).

In vitro studies have indicated netarsudil has the potential to inhibit CYP450 isoenzymes in the cornea, however no clinical evidence of local pharmacokinetic interactions has been observed to date.

There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of latanoprost + netarsudil in pregnant women.

No effects during pregnancy are anticipated, since systemic exposure to netarsudil is negligible (see section 5.2). Animal studies with intravenous administration of netarsudil do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures (see section 5.3).

Latanoprost has potentially harmful pharmacological effects during pregnancy and/or on the fetus/newborn child (see section 5.3).

Therefore, latanoprost + netarsudil should not be used during pregnancy.

Breast-feeding

It is unknown whether netarsudil/me­tabolites are excreted in human milk. However, while no effects on the breastfed newborn/infant are anticipated since the systemic exposure of breast-feeding women to netarsudil is expected to be negligible, no relevant clinical data are available (see section 5.2). Latanoprost and its metabolites may pass into human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Roclanda therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of netarsudil on male or female fertility. However, no effects are anticipated, since systemic exposure to netarsudil is negligible (see section 5.2). Latanoprost has not been found to have any effect on male or female fertility in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Roclanda has negligible influence on the ability to drive and use machines.

If transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

The most common ocular adverse reaction observed is conjunctival hyperemia which was reported in 52% of patients. Other ocular adverse reactions reported are instillation site pain (18%), cornea verticillata (13%), eye pruritis

(6%), instillation site erythema (6%), increased lacrimation (5%), instillation site discomfort (5%) and conjunctival haemorrhage (4%).

Tabulated list of adverse reactions

The following adverse reactions have been reported with latanoprost + netarsudil, dosed once daily, and during clinical studies and post-marketing surveillance with the individual components latanoprost and netarsudil. Adverse reactions are presented according to the MedDRA system organ classification. Within each system organ class, the adverse reactions are classified by frequency 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).___________­___________________

1 See Description of selected adverse reactions for further information 2 Additional adverse reaction observed with latanoprost monotherapy 3 Additional adverse reaction observed with netarsudil monotherapy Description of selected adverse reactions

Conjunctival hyperaemia

Conjunctival hyperaemia was the most frequently reported adverse reaction associated with latanoprost + netarsudil treatment in clinical studies and it is attributed to the vasodilation effect of the Rho kinase inhibitor medicinal product class. Conjunctival hyperaemia was typically mild in severity and sporadic. However, there was a relatively small proportion of subjects with moderate or severe hyperaemia who discontinued treatment because of this adverse reaction (5.0% in Phase 3 clinical studies).

Cornea verticillata

Cornea verticillata occurred in approximately 13% of the patients in controlled Phase 3 clinical studies. The cornea verticillata seen in latanoprost + netarsudil-treated patients were first noted at 4 weeks of daily dosing. This reaction did not result in any apparent visual functional changes in patients. The majority of cornea verticillata resolved upon discontinuation of treatment. The incidence of cornea verticillata was higher in certain subpopulations: elderly (>65 years) versus non-elderly (18.8 vs. 11.5%); males versus females (18.8 vs. 13.0%) and in white versus other races (21.7 vs. 2.5%).

Iris pigmentation

Roclanda contains latanoprost which is a prostaglandin F2a analogue. The majority of adverse reactions associated with latanoprost are ocular in nature. In a 5-year latanoprost safety study, 33% of patients developed iris pigmentation (section 4.4).

This change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In studies with latanoprost, the onset of the change is usually within the first 8 months of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable for five years. The effect of increased pigmentation beyond five years has not been evaluated. The iris colour change is slight in the majority of cases and often not observed clinically. The incidence in patients with mixed colour irides ranged from 7 to 85%, with yellow-brown irides having the highest incidence. In patients with homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown eyes, the change has only rarely been seen.

The colour change is due to increased melanin content in the stromal melanocytes of the iris and not to an increase in number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. No further increase in brown iris pigment has been observed after discontinuation of treatment. It has not been associated with any symptom or pathological changes in clinical studies to date.

Neither naevi nor freckles of the iris have been affected by treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in clinical studies.

Other special populations

Elderly

With the exception of cornea verticillata (see above), no difference in the safety profile for latanoprost + netarsudil has been observed between subjects aged <65 or >65 years.

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Absorption

The systemic exposures of netarsudil and its active metabolite, AR-13503, were evaluated in 18 healthy subjects after topical ocular administration of netarsudil 200 micrograms/ml once daily (one drop bilaterally in the morning) for 8 days. There were no quantifiable plasma concentrations of netarsudil (lower limit of quantitation (LLOQ) 0.100 ng/ml) post dose on Day 1 and Day 8. Only one plasma concentration at 0.11 ng/ml for the active metabolite was observed for one subject on Day 8 at 8 hours post-dose.

Latanoprost (molecular weight 432.58) is an isopropyl ester prodrug which per se is inactive, but after hydrolysis to the acid of latanoprost becomes biologically active. The prodrug is well absorbed through the cornea and all active substance that enters the aqueous humour is hydrolysed during the passage through the cornea. Studies in man indicate that the peak concentration in the aqueous humour is reached about two hours after topical administration. After topical application in monkeys, latanoprost is distributed primarily in the anterior segment, the conjunctivae and the eyelids. Only minute quantities of latanoprost reach the posterior segment.

Biotransformation

After topical ocular dosing, netarsudil is metabolized by esterases in the eye to an active metabolite, AR-13503.

There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The half-life in plasma is 17 minutes in man. The main metabolites, the 1,2-dinor and 1,2,3,4-tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine.

5.3 Preclinical safety data

Netarsudil

Non-clinical data with netarsudil reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to development. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Intravenous administration of netarsudil to pregnant rats and rabbits during organogenesis did not produce adverse embryofetal effects at clinically relevant systemic exposures. In pregnant rats, 0.1 mg/kg/day showed no adverse maternal or embryofoetal effects, whereas increased post-implantation loss and reduced foetal viability was observed at 0.3 mg/kg/day and higher.

In pregnant rabbits, 3 mg/kg/day showed no maternal or embryofoetal effects, whereas an increase in post-implantation loss and a decrease in foetal weight were observed at 5 mg/kg/day.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of netarsudil.

Netarsudil was not mutagenic in a bacterial mutation assay, in a mouse lymphoma assay, or in a rat micronucleus test.

Netarsudil and its active metabolite AR-13503 was found to have a possible phototoxic potential in a modified 3T3 NRU-PT in vitro assay, where the wavelength was extended to include UVB light.

Latanoprost

The ocular as well as systemic toxicity of latanoprost has been investigated in several animal species. Generally, latanoprost is well tolerated with a safety margin between clinical ocular dose and systemic toxicity of at least 1000 times. High doses of latanoprost, approximately 100 times the clinical dose/kg body weight, administered intravenously to unanaesthetised monkeys have been shown to increase the respiration rate probably reflecting bronchoconstriction of short duration. In animal studies, latanoprost has not been found to have sensitising properties.

In the eye, no toxic effects have been detected with doses of up to 100 microgram­s/eye/day in rabbits or monkeys (clinical dose is approximately 1.5 microgram­s/eye/day). In monkeys, however, latanoprost has been shown to induce increased pigmentation of the iris. The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris with no proliferative changes observed. The change in iris colour may be permanent.

In chronic ocular toxicity studies, administration of latanoprost

6 micrograms/e­ye/day has also been shown to induce increased palpebral fissure. This effect is reversible and occurs at doses above the clinical dose level. The effect has not been seen in humans.

Latanoprost was found negative in reverse mutation tests in bacteria, gene mutation in mouse lymphoma and mouse micronucleus test. Chromosome aberrations were observed in vitro with human lymphocytes. Similar effects were observed with prostaglandin F2a, a naturally occurring prostaglandin, and indicates that this is a class effect.

Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were negative and indicate that latanoprost does not have mutagenic potency. Carcinogenicity studies in mice and rats were negative.

Latanoprost has not been found to have any effect on male or female fertility in animal studies. In the embryotoxicity study in rats, no embryotoxicity was observed at intravenous doses (5, 50 and 250 microgram­s/kg/day) of latanoprost. However, latanoprost induced embryolethal effects in rabbits at doses of 5 micrograms/kg/day and above.

The dose of 5 micrograms/kg/day (approximately 100 times the clinical dose) caused significant embryofoetal toxicity characterised by increased incidence of late resorption and abortion and by reduced foetal weight.

No teratogenic potential has been detected.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzalkonium chloride

Mannitol

Boric acid

Sodium hydroxide (for pH adjustment) Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

Opened bottle: 4 weeks after first opening the bottle. Do not store above 25 or1

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C). Store in the original carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Roclanda is supplied in clear low density polyethylene bottles (2.5 ml fill in a 4 ml container), opaque white low density polyethylene tips with opaque white polypropylene screw caps and anti-tamper seals.

Carton containing 1 bottle.