Leaflet ROCLANDA 50mcg / ml+200mcg / ml ophthalmic drops solution

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

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

Each ml of solution contains 200 micrograms benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops, solution (eye drops).

Clear, colourless solution, pH 5 (approximately).

Osmolality: 280 mOsm/Kg.

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

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

The recommended dose is one drop in the affected eye(s) once daily in the evening. Patients shouldnot instil 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.

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

No data are available.

For ocular use.

Data on potential interactions specific to latanoprost + netarsudil are described in section 4.5. Iflatanoprost + 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’svasodilating properties, other eye drops should be administered before latanoprost + netarsudil. Eyeointments should be administered last.

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

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

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

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

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 ineye colour. Unilateral treatment can result in permanent heterochromia.

Increased iris pigmentation has not been shown to have any negative clinical sequelae and treatmentwith 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 medicinalproducts containing latanoprost may be discontinued.

Herpetic keratitis condition

Medicinal product(s) containing latanoprost should be used with caution in patients with a history ofherpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients witha 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 inaphakic 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 andretinal vein occlusion). Medicinal products containing latanoprost should be used with caution inaphakic 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 containinglatanoprost can be used with caution.

Asthma exacerbation

There is limited experience of latanoprost use in patients with asthma, but some cases of exacerbationof asthma and/or dyspnoea were reported in post marketing experience. Asthmatic patients shouldtherefore 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 containinglatanoprost, the majority of reports being in Japanese patients. Experience to date shows thatperiorbital skin discolouration is not permanent and in some cases has reversed while continuingtreatment with latanoprost.

Eyelash changes

Treatment with medicinal products containing latanoprost may gradually change eyelashes and vellushair 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 arereversible upon discontinuation of treatment.

Reticular epithelial corneal oedema

Reticular epithelial corneal oedema (RECE) has been reported following administration of medicinalproducts containing netarsudil, particularly in patients with preexisting corneal oedema or prior ocularsurgery. RECE typically resolves upon discontinuation of the medicinal product containing netarsudil.

Patients should be advised to notify their physician if they experience decreased vision or eye painwhile using Roclanda.

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

This medicinal product contains benzalkonium chloride.

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

Patients should be monitored in case of prolonged use.

In vitro interaction studies have shown that precipitation can occur when eye drops containingthiomersal are mixed with latanoprost + netarsudil. Administer other eye drops at least five minutesapart (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 ophthalmicadministration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins,prostaglandin analogues or prostaglandin derivatives is not recommended.

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 (seesection 5.2). Animal studies with intravenous administration of netarsudil do not indicate direct orindirect harmful effects with respect to reproductive toxicity at clinically relevant exposures (seesection 5.3).

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

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

It is unknown whether netarsudil/metabolites are excreted in human milk. However, while no effectson the breastfed newborn/infant are anticipated since the systemic exposure of breast-feeding womento 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 todiscontinue breast-feeding or to discontinue/abstain from Roclanda therapy taking into account thebenefit of breast feeding for the child and the benefit of therapy for the woman.

There are no data on the effects of netarsudil on male or female fertility. However, no effects areanticipated, since systemic exposure to netarsudil is negligible (see section 5.2). Latanoprost has notbeen found to have any effect on male or female fertility in animal studies (see section 5.3).

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 beforedriving or using machines.

The most common adverse reactions observed in the clinical studies were conjunctival hyperaemia(46% of patients), instillation site pain (14%), cornea verticillata (12%) and eye pruritis (7%). Seriousadverse reactions were not reported in clinical studies.

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 latanoprostand 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 thefollowing 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 fromthe available data).

System organ classification Frequency Adverse reactions

Infections and infestations Rare Herpetic keratitis2

Immune system disorders Uncommon Hypersensitivity

Nervous system disorders Uncommon Headache,

Muscle contractions involuntary,

Dizziness,

Visual field defect3

System organ classification Frequency Adverse reactions

Eye disorders Very Conjunctival hyperaemia1,common Cornea verticillata1,

Instillation site pain,

Iris hyperpigmentation2,

Eyelash and vellus hair changes of theeyelid (increased length, thickness,pigmentation and number ofeyelashes)2

Common Conjunctival haemorrhage,

Vision blurred,

Lacrimation increased,

Erythema of eyelid,

Eye pruritus,

Eye irritation,

Visual acuity reduced,

Eyelid oedema,

Punctate keratitis,

Corneal disorder,

Conjunctival oedema,

Conjunctivitis allergic,

Eye pain,

Dry eye,

Foreign body sensation in eyes,

Eyelid margin crusting,

Blepharitis,

Instillation site erythema,

Instillation site discomfort,

Vital dye staining cornea present

Uncommon Eyelids pruritus,

Conjunctival disorder,

Corneal opacity,

Eye discharge,

Corneal deposits,

Conjunctivitis,

Dacryostenosis acquired,

Eye inflammation,

Eye paraesthesia,

Conjunctival follicles,

Eye swelling,

Meibomian gland dysfunction,

Corneal pigmentation,

Diplopia,

Noninfective conjunctivitis,

Abnormal sensation in eye,

Keratitis,

Refraction disorder,

Anterior chamber flare,

Conjunctival irritation,

Intraocular pressure increased,

Eyelid rash,

Eyelid skin dryness,

Growth of eyelashes,

Lacrimal disorder,

Iritis,

Visual impairment,

Corneal dystrophy,

System organ classification Frequency Adverse reactions

Instillation site dryness,

Instillation site pruritus,

Instillation site reaction,

Eye complication associated withdevice, fatigue,

Instillation site paraesthesia,

Macular oedema including cystoidmacular oedema2,

Uveitis2

Ocular hyperaemia

Diabetic retinopathy3,

Eye allergy3

Ocular discomfort,

Eyelid disorder3,

Ectropion3,

Lenticular opacities3,

Asthenopia3,

Episcleral hyperaemia3,

Halo vision3,

Anterior chamber inflammation3,

Blindness3,

Conjunctivochalasis,

Eczema eyelids3,

Glaucoma3,

Iris adhesions3,

Iris bombe3,

Ocular hypertension3,

Instillation site irritation3,

Glassy eyes3,

Instillation site oedema3,

Conjunctival staining3,

Optic nerve cup/disc ratio increased3,

Madarosis3,

Blepharal pigmentation,

Eye disorder,

Retinal haemorrhage,

Photophobia

Rare Corneal oedema2,

Corneal erosion2,

Periorbital oedema2,

Trichiasis2,

Distichiasis2,

Iris cyst2,

Localised skin reaction on theeyelids2,

Darkening of the palpebral skin of theeyelids2,

Pseudopemphigoid of ocularconjunctiva2

Very rare Periorbital and lid changes resultingin deepening of the eyelid sulcus2

Not known Reticular epithelial corneal oedema3

Cardiac disorders Uncommon Angina2,

Palpitations2

Very rare Angina unstable2

Uncommon Epistaxis,

System organ classification Frequency Adverse reactions

Respiratory, thoracic and mediastinal Nasal congestion,disorders Nasal discomfort3,

Rhinalgia3

Asthma2,

Dyspnoea2

Rare Asthma exacerbation2

Gastrointestinal disorders Uncommon Nausea,

Skin and subcutaneous tissue disorders Common Dermatitis contact

Uncommon Lichenification,

Dry skin,

Erythema,

Skin disorder,

Dermatitis allergic3

Petechiae,

Eczema

Rare Pruritus2

Musculoskeletal and connective tissue Uncommon Pain in jaw,disorders Myalgia2,

Arthralgia2,

Polychondritis3,

Muscular weakness,

Sjogren’s syndrome

General disorders and administration site Uncommon Chest pain2conditions

Injury, poisoning and procedural Uncommon Excoriation3complications1 See Description of selected adverse reactions for further information2 Additional adverse reaction observed with latanoprost monotherapy3 Additional adverse reaction observed with netarsudil monotherapy

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 kinaseinhibitor 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 whodiscontinued treatment because of this adverse reaction (5% 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 ofdaily dosing. This reaction did not result in any apparent visual functional changes in patients. Themajority of cornea verticillata resolved upon discontinuation of treatment. The incidence of corneaverticillata 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 F2α analogue. The majority of adverse reactionsassociated with latanoprost are ocular in nature. In a 5-year latanoprost safety study, 33% of patientsdeveloped 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 thechange is usually within the first 8 months of treatment, rarely during the second or third year, and hasnot been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreaseswith time and is stable for five years. The effect of increased pigmentation beyond five years has notbeen evaluated. The iris colour change is slight in the majority of cases and often not observedclinically. 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 hasbeen observed and in patients with homogeneously grey, green or brown eyes, the change has onlyrarely been seen.

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

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

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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Systemic exposure to the netarsudil component of latanoprost + netarsudil following topical ocularadministration has been shown to be negligible.

Apart from ocular irritation and conjunctival hyperaemia, no other ocular side effects are known iflatanoprost is overdosed.

If latanoprost is accidentally ingested the following information may be useful: one bottle contains125 micrograms latanoprost. More than 90% is metabolised during the first pass through the liver.

Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating.

In monkeys, latanoprost has been infused intravenously in doses of up to 500 micrograms/kg withoutmajor effects on the cardiovascular system.

Intravenous administration of latanoprost in monkeys has been associated with transientbronchoconstriction. However, in patients with moderate bronchial asthma, bronchoconstriction wasnot induced by latanoprost when applied topically on the eyes in a dose of seven times the clinicaldose of latanoprost.

If topical overdose of latanoprost + netarsudil should occur, the eye(s) may be flushed with tap water.

Treatment of an overdose would include supportive and symptomatic therapy.

Pharmacotherapeutic group: Ophthalmologicals, antiglaucoma preparations and miotics, ATC code:

S01EE51

Roclanda contains two active substances: latanoprost and netarsudil. These two components lower

IOP by increasing the outflow of aqueous humor. Although both latanoprost and netarsudil lower IOPby increasing aqueous humor outflow, their mechanisms of action are different.

Studies in animal and man suggest that the main mechanism of action for netarsudil, a Rho kinaseinhibitor, is increased trabecular outflow. These studies also suggest that netarsudil lowers IOP byreducing episcleral venous pressure.

Studies in animal and man indicate that the main mechanism of action for latanoprost, a prostaglandin

F2α analoque, is increased uveoscleral outflow, although some increase in outflow facility (decrease inoutflow resistance) has been reported in man.

Roclanda was evaluated in 3 randomized, double-blind, multicentre Phase 3 clinical studies in1 686 patients with open-angle glaucoma and ocular hypertension. Studies 301 and 302 enrolledsubjects with IOP < 36 mmHg and compared IOP lowering effect of latanoprost + netarsudil dosedonce daily to individually administered netarsudil 0.02% once daily and latanoprost 0.005% oncedaily. The treatment duration was 12 months for Study 301 and 3 months for Study 302. The medianage of study participants was 66 years (range 18 to 99 years). Study 303 assessed the ocularhypotensive efficacy of latanoprost + netarsudil relative to bimatoprost 0.03%/timolol 0.5%. Thetreatment duration was 6 months.

Studies 301 and 302 were designed to show superiority of latanoprost + netarsudil when dosed oncedaily in the evening over its individual components netarsudil 0.02% once daily and latanoprost0.005% once daily. The primary efficacy outcome measure was least squares (LS) mean IOP at eachof 9 timepoints measured at 08:00, 10:00 and 16:00 on day 15, day 43 and day 90. The average IOPlowering effect of latanoprost + netarsudil was 1 to 3 mmHg greater than monotherapy with eithernetarsudil 0.02% or latanoprost 0.005% throughout 3 months (Figures 1 and 2). In Study 301 IOPreductions were maintained, showing statistical superiority of latanoprost + netarsudil throughout the12-month treatment period. In all cases, the differences in the LS mean IOP were clinically relevantand statistically significant (p < 0.0001) through month 3. Approximately 30% of subjects included inthe Phase 3 studies had a baseline IOP of ≥ 27 mmHg (132, 136 and 143 in the latanoprost +netarsudil, latanoprost and netarsudil treatment groups, respectively). In these subjects, latanoprost +netarsudil showed statistically significantly superior IOP-lowering efficacy to each of its componentsat all time points. Across both studies, compared to latanoprost alone, the combination productreduced IOP by a further 1.7 mmHg to 3.7 mmHg, and compared to netarsudil alone by a further3.4 mmHg to 5.9 mmHg.

Figure 1: Study 301 mean IOP (mmHg) by treatment group and treatment difference in mean IOP

Roclanda Netarsudil Latanoprost

Baseline Baseline Baseline22 8AM 10AM 4PM 8AM 10AM 4PM 8AM 10AM 4PM24.8 23.7 22.6 24.8 23.5 22.6 24.6 23.4 22.419.1 19.318.6 18.418 17.9 18.117.8 17.7 17.6 17.617 17.4 17.2 17.117.0 16.9 17.417.2 16.716 16.0 16.115.6 15.215 14.9 15.3 15.414.8 15.2

Day 15 Day 15 Day 15 Day 43 Day 43 Day 43 Day 90 Day 90 Day 90(8AM) (10AM) (4PM) (8AM) (10AM) (4PM) (8AM) (10AM) (4PM)latanoprost +3.0 3.0 2.4 3.2 2.9 2.3 3.1 3.2 2.0netarsudil vs.

netarsudil(2.5, 3.6) (2.4, 3.6) (1.9, 3.0) (2.6, 3.8) (2.3, 3.5) (1.7, 2.8) (2.5, 3.8) (2.5, 3.8) (1.4, 2.6)95% CIlatanoprost +2.3 2.6 2.3 1.7 1.9 1.7 1.5 1.7 1.3netarsudil vs.

latanoprost(1.7, 2.8) (2.0, 3.2) (1.8, 2.9) (1.1, 2.4) (1.3, 2.5) (1.1, 2.2) (0.9, 2.1) (1.1, 2.3) (0.7, 1.9)95% CI

The LS mean IOP at each post-baseline time point was derived using an analysis of covariance adjusted for baseline IOP and based onobserved data for all randomized subjects (238 in latanoprost + netarsudil group, 244 in netarsudil group, 236 in latanoprost group).

Figure 2: Study 302 mean IOP (mmHg) by treatment group and treatment difference in mean IOP23 Roclanda Netarsudil Latanoprost22 Baseline Baseline Baseline8AM 10AM 4PM 8AM 10AM 4PM 8AM 10AM 4PM21 24.7 23.3 22.4 24.7 23.4 22.8 24.8 23.2 22.620 20.019.4 19.618.4 18.418.118 18.0 17.9 17.917.9 18.017.4 17.517 17.7 17.517.1 17.1 17.116.4 16.416 16.115.5 15.615 15.3 15.2 15.5 15.6

Day 15 Day 15 Day 15 Day 43 Day 43 Day 43 Day 90 Day 90 Day 90(8AM) (10AM) (4PM) (8AM) (10AM) (4PM) (8AM) (10AM) (4PM)latanoprost +3.4 2.7 2.2 3.2 2.9 2.3 3.6 2.8 2.4netarsudil vs.

netarsudil(2.8, 3.9) (2.2, 3.2) (1.7, 2.8) (2.6, 3.8) (2.3, 3.4) (1.8, 2.9) (3.0, 4.2) (2.3, 3.4) (1.9, 2.9)95% CIlatanoprost +2.0 2.4 1.9 1.5 1.9 1.6 1.5 2.0 1.5netarsudil vs.

latanoprost(1.5, 2.6) (1.9, 2.9) (1.3, 2.4) (0.9, 2.1) (1.3, 2.4) (1.0, 2.1) (0.9, 2.2) (1.4, 2.5) (1.0, 2.1)95% CI

The LS mean IOP at each post-baseline time point was derived using an analysis of covariance adjusted for baseline IOP and based onobserved data for all randomized subjects (245 in latanoprost + netarsudil group, 255 in netarsudil group, 250 in latanoprost group).

Approximately 67% of subjects included in the latanoprost + netarsudil treatment groups of Phase 3studies were caucasian and 30% black or african american. Over half were aged ≥ 65 years. With theexception of the incidence of cornea verticillata (section 4.8); no other difference in safety profile wasobserved between races or age groups.

Completion rates in studies 301 and 302 were lower in the latanoprost + netarsudil treatment groupswhen compared with the latanoprost group. Discontinuation rates due to adverse events at month 3were 8.7% for the pooled latanoprost + netarsudil treatment group versus 7.6% for the poolednetarsudil group and 1.0% for the pooled latanoprost group. Discontinuation rates due to adverseevents at month 12 in Study 301 were 19.7% for the latanoprost + netarsudil treatment group versus21.7% for the netarsudil group and 1.7% for the latanoprost group. The majority of discontinuationswere associated with ocular events. The most frequently reported adverse event associated withdiscontinuation in the latanoprost + netarsudil group was conjunctival hyperemia (7.6% at month 12).

The majority of ocular adverse events reported with netarsudil + latanoprost were mild in intensity.

Study 303 was a prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, 6-month study assessing the safety and ocular hypotensive efficacy of latanoprost + netarsudilcompared to bimatoprost + timolol in 430 subjects with elevated intraocular pressure. Subjects wererandomly assigned to a planned fixed-dose treatment regimen with latanoprost + netarsudil one drop(218 subjects), once daily (QD) each evening in both eyes (OU) or comparator bimatoprost + timolol(212 subjects) one drop QD each evening OU for approximately 180 days following a washout period.

The primary efficacy outcome was the comparison of latanoprost + netarsudil to bimatoprost + timololfor Mean IOP at specified timepoints at Week 2, Week 6, and Month 3. The primary analysis wasperformed on the ITT population with imputation by Markov Chain Monte Carlo (MCMC) method.

This analysis demonstrated clinical non-inferiority of latanoprost + netarsudil ophthalmic solutionrelative to bimatoprost + timolol dosed QD in the ITT population with the upper limit of the 95% CIsaround the difference (latanoprost + netarsudil - bimatoprost + timolol) ≤ 1.5 mmHg at all 9 timepoints and ≤ 1.0 mmHg at the majority (6 out of 9) of time points from Week 2 through Month 3,meeting the criteria for success. The threshold for clinical non-inferiority of latanoprost + netarsudil

QD relative to bimatoprost + timolol QD (the between-group difference ≤ 1.5 mmHg) wasdemonstrated in the PP population at 8 out of 9 time points (08:00, 10.00, and 16:00) at week 2,through month 3 using the MCMC method. However, clinical non inferiority was not met overallsince at the week 6 08:00 time point, the upper bound 95% CI was 1.55. Overall, there was a similarmean IOP reduction throughout the day of approximately 9.5 mmHg between both the latanoprost +netarsudil and bimatoprost + timolol treatment group.

The overall rate of discontinuation from the study treatment due to a TEAE was 11.2%. More subjectsin the latanoprost + netarsudil QD treatment group d iscontinued from the study treatment due to a

TEAE (20.2%) compared to t he bimatoprost + timolol QD group (1.9%), and the majority of TEAEsleading to discontinuation were ocular TEAEs. No serious treatment-related adverse events werereported in any treatment group, and the safety profile remains consistent with the known profile forlatanoprost + netarsudil, and/or latanoprost or netarsudil alone.

The efficacy and safety of latanoprost + netarsudil in subjects with compromised corneal epithelium orco-existing ocular pathologies e.g. pseudoexfoliation and dispersion pigment syndrome has not beenestablished.

The European Medicines Agency has waived the obligation to submit the results of studies with

Roclanda in all subsets of the paediatric population for the reduction of elevated intraocular pressurein patients with open-angle glaucoma or ocular hypertension (see section 4.2 for information onpaediatric use).

The systemic exposures of netarsudil and its active metabolite, AR-13503, were evaluated in18 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 ofnetarsudil (lower limit of quantitation (LLOQ) 0.100 ng/ml) post dose on Day 1 and Day 8. Only oneplasma concentration at 0.11 ng/ml for the active metabolite was observed for one subject on Day 8 at8 hours post-dose.

Latanoprost (molecular weight 432.58) is an isopropyl ester prodrug which per se is inactive, but afterhydrolysis to the acid of latanoprost becomes biologically active. The prodrug is well absorbedthrough the cornea and all active substance that enters the aqueous humour is hydrolysed during thepassage through the cornea. Studies in man indicate that the peak concentration in the aqueous humouris 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. Onlyminute quantities of latanoprost reach the posterior segment.

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 occursin the liver. The half-life in plasma is 17 minutes in man. The main metabolites, the 1,2-dinor and1,2,3,4-tetranor metabolites, exert no or only weak biological activity in animal studies and areexcreted primarily in the urine.

Netarsudil

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

Intravenous administration of netarsudil to pregnant rats and rabbits during organogenesis did notproduce adverse embryofetal effects at clinically relevant systemic exposures. In pregnant rats,0.1 mg/kg/day showed no adverse maternal or embryofoetal effects, whereas increasedpost-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 inpost-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 ofnetarsudil.

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

Netarsudil and its active metabolite AR-13503 was found to have a possible phototoxic potential in amodified 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 systemictoxicity of at least 1 000 times. High doses of latanoprost, approximately 100 times the clinicaldose/kg body weight, administered intravenously to unanaesthetised monkeys have been shown toincrease the respiration rate probably reflecting bronchoconstriction of short duration. In animalstudies, 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 rabbitsor 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 increasedpigmentation seems to be stimulation of melanin production in melanocytes of the iris with noproliferative changes observed. The change in iris colour may be permanent.

In chronic ocular toxicity studies, administration of latanoprost 6 micrograms/eye/day has also beenshown to induce increased palpebral fissure. This effect is reversible and occurs at doses above theclinical dose level. The effect has not been seen in humans.

Latanoprost was found negative in reverse mutation tests in bacteria, gene mutation in mouselymphoma and mouse micronucleus test. Chromosome aberrations were observed in vitro with humanlymphocytes. Similar effects were observed with prostaglandin F2α, a naturally occurringprostaglandin, and indicates that this is a class effect.

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

Latanoprost has not been found to have any effect on male or female fertility in animal studies. In theembryotoxicity study in rats, no embryotoxicity was observed at intravenous doses (5, 50 and250 micrograms/kg/day) of latanoprost. However, latanoprost induced embryolethal effects in rabbitsat doses of 5 micrograms/kg/day and above.

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

No teratogenic potential has been detected.

Mannitol (E 421)

Boric acid

Sodium hydroxide (E 524) (for pH adjustment)

Water for injections

Not applicable.

3 years.

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

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.

Roclanda is supplied (sterile) in low density polyethylene bottles (2.5 ml fill) and tips with whitepolypropylene screw caps and anti-tamper seals or in polypropylene bottles (2.5 ml fill) and tips withwhite high density polyethylene screw caps and anti-tamper seals.

Carton containing 1 or 3 bottles. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Santen Oy

Niittyhaankatu 2033720 Tampere

Finland

EU/1/20/1502/001

EU/1/20/1502/002

EU/1/20/1502/003

EU/1/20/1502/004

Date of first authorisation: 7 January 2021

Date of latest renewal: 14 August 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.