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

The recommended dose is one drop in the affected eye(s) once daily in the evening. Patients should not 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.

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 substances 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.

Reticular epithelial corneal oedema

Reticular epithelial corneal oedema (RECE) has been reported following administration of medicinal products containing netarsudil, particularly in patients with preexisting corneal oedema or prior ocular surgery. 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 pain while using Roclanda.

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

Excipient with known effect

Benzalkonium chloride

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.

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

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) or not known (cannot be estimated from the 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

Eye disorders

Very common

Conjunctival hyperaemia1,

Cornea verticillata1,

Instillation site pain,

Iris hyperpigmentation2,

Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation and number of eyelashes)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,

Instillation site dryness,

Instillation site pruritus,

Instillation site reaction,

Eye complication associated with device, fatigue,

Instillation site paraesthesia,

Macular oedema including cystoid macular 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 the eyelids2,

Darkening of the palpebral skin of the eyelids2,

Pseudopemphigoid of ocular conjunctiva2

Very rare

Periorbital and lid changes resulting in deepening of the eyelid sulcus2

Not known

Reticular epithelial corneal oedema3

Cardiac disorders

Uncommon

Angina2,

Palpitations2

Very rare

Angina unstable2

Respiratory, thoracic and mediastinal disorders

Uncommon

Epistaxis,

Nasal congestion,

Nasal discomfort3,

Rhinalgia3

Asthma2,

Dyspnoea2

Rare

Asthma exacerbation2

Gastrointestinal disorders

Uncommon

Nausea,

Vomiting

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 disorders

Uncommon

Pain in jaw,

Myalgia2,

Arthralgia2,

Polychondritis3,

Muscular weakness,

Sjogren's syndrome

General disorders and administration site conditions

Uncommon

Chest pain2

Injury, poisoning and procedural complications

Uncommon

Excoriation3

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% 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 F2α 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

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

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

If latanoprost is accidentally ingested the following information may be useful: one bottle contains 125 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 of 5.5-10 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 without major effects on the cardiovascular system.

Intravenous administration of latanoprost in monkeys has been associated with transient bronchoconstriction. However, in patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost when applied topically on the eyes in a dose of seven times the clinical dose 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.