Ranibizumab

Registered South African indications:

• Neovascular (wet) age-related macular degeneration (AMD)
• Visual impairment due to diabetic macular oedema (DME)
• Non-proliferative diabetic retinopathy (NPDR)
• Proliferative diabetic retinopathy (PDR)
• Visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO)
• Visual impairment due to choroidal neovascularization
• Visual impairment due to choroidal neovascularization (CNV) secondary to pathologic myopia (PM)
• Retinopathy of prematurity (ROP)

Contraindications 

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Active or suspected ocular or periocular infections
• Active severe intraocular inflammation

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Active or suspected ocular or periocular infections
• Active severe intraocular inflammation

Cautions

International manufacturer recommendations

• Risk for developing hypersensitivity (especially for diabetic macular oedema patients)
• Pregnancy
• Breastfeeding
• Hepatic impairment
• Elderly
  - ≥75 years with diabetic macular oedema
• Aseptic injection technique
• Decrease in best corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity
• Intraocular pressure of ≥30mmHg
• Retinal break
• Subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area
• Performed or planned intraocular surgery within the previous or next 28 days
• Risk factors for retinal pigment epithelial tear
  - Large or high pigment epithelial retinal detachment
• Rhegmatogenous retinal detachment or stage 3 or 4 macular holes
• Usage in preterm infants beyond 2 years
• Previous intravitreal injections
• Active systemic infections
• Diabetic macular oedema (DME) due to type 1 diabetes
• Concurrent eye conditions such as retinal detachment or macular hole
• Diabetic patients with HbA1c >108 mmol/mol (12%)
• Uncontrolled hypertension
• Retinal vein occlusion patients presenting with irreversible ischaemic visual function loss
• Pathologic myopia patients with
  - Previously unsuccessful verteporfin photodynamic therapy (vPDT) 
  - Extrafoveal lesions
  - Prior history of stroke or transient ischaemic attacks
• Coadministration with other anti-vascular endothelial growth factors (anti-VEGF)
• May impair ability to drive or operate machinery

South African manufacturer recommendations

• Risk for developing hypersensitivity (especially for diabetic macular oedema patients) 
• Hepatic impairment
• Elderly
  - ≥75 years with diabetic macular oedema
• Aseptic injection technique
• Decrease in best corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity
• Intraocular pressure of ≥30mmHg
• Retinal break
• Subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area
• Performed or planned intraocular surgery within the previous or next 28 days
• Risk factors for retinal pigment epithelial tear
  - Large or high pigment epithelial retinal detachment
• Rhegmatogenous retinal detachment or stage 3 or 4 macular holes
• Long term use in preterm infants
• Previous intravitreal injections
• Active systemic infections
• Diabetic macular oedema (DME) due to type 1 diabetes
• Concurrent eye conditions such as retinal detachment or macular hole
• Diabetic patients with HbA1c >108 mmol/mol (12%)
• Uncontrolled hypertension
• Retinal vein occlusion patients presenting with irreversible ischaemic visual function loss
• Pathologic myopia patients with;
  - Previously unsuccessful verteporfin photodynamic therapy (vPDT)
  - Extrafoveal lesions
  - Prior history of stroke or transient ischaemic attacks
• Coadministration with other anti-vascular endothelial growth factors (anti-VEGF)
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Neovascular (wet) age-related macular degeneration (AMD)
Visual impairment due to diabetic macular oedema (DME)
Proliferative diabetic retinopathy (PDR)
Visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)
Visual impairment due to choroidal neovascularization

• Intravitreal (inj): 0.5mg, monthly

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Ranibizumab must be administered by a qualified ophthalmologist experienced in intravitreal injections

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A 0.5mg dose corresponds to an injection volume of 0.05ml

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The interval between 2 doses injected into the same eye should be at least 4 weeks

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Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treatment

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In patients with wet AMD, DME, NPDR or PDR and RVO, initially, three or more consecutive, monthly injections may be needed

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See additional prescribing points

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South African manufacturer recommendations

Neovascular (wet) age-related macular degeneration (AMD)
Visual impairment due to diabetic macular oedema (DME)
Non-proliferative diabetic retinopathy (NPDR) - moderately severe to severe
Proliferative diabetic retinopathy (PDR) - moderately severe to severe
Visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO)
Visual impairment due to choroidal neovascularization
Visual impairment due to choroidal neovascularization (CNV) secondary to pathologic myopia (PM)

• Intravitreal (inj): 0.5mg, monthly

---

Ranibizumab must be administered by a qualified ophthalmologist experienced in intravitreal injections

---

A 0.5mg dose corresponds to an injection volume of 0.05ml

---

The interval between 2 doses injected into the same eye should be at least 4 weeks

---

Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treatment

---

In patients with wet AMD, DME, NPDR or PDR and RVO, initially, three or more consecutive, monthly injections may be needed

---

See additional prescribing points

Paed. forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Retinopathy of prematurity with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+) or aggressive posterior retinopathy of prematurity disease

• Intravitreal (inj): Initial: 0.2mg per eye

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A 0.2mg dose corresponds to an injection volume of 0.02ml

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Not established for use in children <18 years for indications other than retinopathy of prematurity

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Injections may be given bilaterally on the same day

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Interval between 2 doses injected into the same eye should be at least 4 weeks

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In total, up to 3 injections per eye may be administered within 6 months of treatment initiation if there are signs of disease activity. The administration of >3 injections per eye has not been studied

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South African manufacturer recommendations

Retinopathy of prematurity (ROP)

• Intravitreal (inj): Initial: 0.2mg per eye

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A 0.2mg dose corresponds to an injection volume of 0.02ml

---

Not established for use in children <18 years for indications other than retinopathy of prematurity

---

Injections may be given bilaterally on the same day

---

Interval between 2 doses injected into the same eye should be at least 4 weeks

---

In total, up to 3 injections per eye may be administered within 6 months of treatment initiation if there are signs of disease activity. The administration of >3 injections per eye has not been studied

Pregnancy

International manufacturer recommendations

• Caution; not recommended 
• For ranibizumab, no clinical data on exposed pregnancies are available
• Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development
• The systemic exposure to ranibizumab is low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentially teratogenic and embryo-/foetotoxic
• Therefore, ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus
• Women of childbearing potential should use effective contraception during treatment
• For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child

South African manufacturer recommendations

• Contraindicated
• Ranibizumab should not be used during pregnancy
• Women who wish to become pregnant and have been treated with ranibizumab should wait at least 3 months after the last dose of ranibizumab
• Women of childbearing potential should use effective contraception during treatment

Breastfeeding

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether ranibizumab is excreted in human milk
• Breastfeeding is not recommended during the use of ranibizumab

South African manufacturer recommendations

• Contraindicated 
• It is not known whether ranibizumab is excreted in human milk. Mothers on ranibizumab should not breastfeed their babies

Fertility

• There is no data available on fertility

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Caution; no information available
  Ranibizumab has not been studied in patients with hepatic impairment. However, no special considerations are needed in this population

Elderly

• Caution; no dose adjustment recommended 
  There is limited experience in patients ≥75 years with diabetic macular oedema

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Anxiety

Cardiovascular Disorders

• Stroke
• Myocardial infarction

Respiratory Disorders

• Nasopharyngitis
• Cough

Gastrointestinal Disorders

• Nausea

Genitourinary Disorders

• Urinary tract infection (observed in DME patients)

Musculoskeletal Disorders

• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Pruritus
• Erythema

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Influenza
• Hypersensitivity

Sensory Disorders

• Increased intraocular pressure
• Vitritis
• Vitreous detachment
• Retinal haemorrhage
• Visual disturbance
• Eye pain
• Vitreous floaters
• Conjunctival haemorrhage
• Eye irritation
• Foreign body sensation in eyes
• Increased lacrimation
• Blepharitis
• Dry eye
• Ocular hyperaemia
• Eye pruritus
• Retinal degeneration
• Retinal disorder
• Retinal detachment
• Retinal tear
• Detachment of the retinal pigment epithelium
• Retinal pigment epithelium tear
• Decreased visual acuity
• Vitreous haemorrhage
• Vitreous disorder
• Uveitis
• Iritis
• Iridocyclitis
• Cataract
• Subcapsular cataract  
• Posterior capsule opacification
• Punctuate keratitis
• Corneal abrasion
• Anterior chamber flare
• Blurred vision
• Injection site haemorrhage
• Eye haemorrhage
• Conjunctivitis
• Allergic conjunctivitis
• Eye discharge
• Photopsia
• Photophobia
• Ocular discomfort
• Eyelid oedema
• Eyelid pain
• Conjunctival hyperaemia
• Blindness  
• Endophthalmitis
• Hypopyon
• Hyphaema
• Keratopathy
• Iris adhesion
• Corneal deposits
• Corneal oedema
• Corneal striae
• Injection site pain
• Abnormal sensation in eye
• Eyelid irritation
• Rhegmatogenous retinal detachment
• Iatrogenic traumatic cataract
• Intraocular inflammation

• Anti-vascular endothelial growth factor (VEGF) treatment
• Verteporfin photodynamic therapy (PDT)

• Intraocular pressure prior to and 30 minutes following injection via tonometry
• Perfusion of the optic nerve head immediately after injection
• Optical coherence tomography
• Fluorescein angiography

Administration considerations

• Monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters
• If in the physician’s opinion, visual and anatomic parameters indicate that the patient is not benefiting from continued treatment, ranibizumab should be discontinued. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography)
• If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur
• The treatment interval should be extended by no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for DME. For NPDR, PDR and RVO, treatment intervals may also be gradually extended, however, there are insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment interval should be shortened accordingly
• The treatment of visual impairment due to CNV should be determined individually per patient based on disease activity
• Some patients may only need one injection during the first 12 months; others may need more frequent treatment, including a monthly injection
• For CNV secondary to pathologic myopia (PM), many patients may only need one or two injections during the first year

Ranibizumab and laser photocoagulation in DME and in macular oedema secondary to BRVO

• There is some experience of ranibizumab administered concomitantly with laser photocoagulation
• When given on the same day, ranibizumab should be administered at least 30 minutes after laser photocoagulation
• Ranibizumab can be administered in patients who have received previous laser photocoagulation

Ranibizumab and verteporfin photodynamic therapy in CNV secondary to PM

• There is no experience of concomitant administration of ranibizumab and verteporfin

Administration directions

1. The patient should be instructed to self-administer antimicrobial drops 6hrly for 3 days before and after each injection
2. Intravitreal injection should only be performed by a specialist
3. The vial is sterile. Do not use the vial if the packaging is damaged since sterility of the vial can no longer be guaranteed. Do not use the vial if the solution is discoloured, cloudy, or contains particulates
4. Before withdrawal, the outer part of the rubber stopper of the vial should be disinfected
5. Attach an 18G needle to a 1ml syringe using aseptic technique
6. The entire contents of the vial should be withdrawn from the vial in an upright position
7. The needle should be discarded and aseptically replaced with a sterile 30G needle
8. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05ml on the syringe. Do not wipe the injection needle. Do not pull back on the plunger
9. The needle should be inserted 3.5-4mm posterior to the limbus into the vitreous cavity avoiding the horizontal meridian and aiming towards the centre of the globe
10. The injection volume of 0.05ml is then delivered
11. The scleral site should be rotated for subsequent injections
12. After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements

Withholding ranibizumab in adults

The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:

• a decrease in best-corrected visual acuity (BCVA) ≥30 letters compared with the last assessment of visual acuity;
• an intraocular pressure of ≥30 mmHg;
• a retinal break;
• a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50% of the total lesion area;
• performed or planned intraocular surgery within the previous or next 28 days

Intravitreal injection-related reactions

• Proper aseptic injection techniques must always be used when administering ranibizumab
• In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs
• Patients should be instructed to report any symptoms suggestive of endophthalmitis, intraocular inflammation without delay

Immunogenicity

• There is a potential for immunogenicity with ranibizumab. Since there is a potential for increased systemic exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient population cannot be excluded
• Patients should also be instructed to report if an intraocular inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody formation

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g. VEGF, VEGF and VEGF), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularization, as well as vascular leakage, all of which are thought to contribute to the progression of the neovascular form of age-related macular degeneration, pathologic myopia and CNV or to visual impairment caused by either diabetic macular oedema or macular oedema secondary to RVO in adults and retinopathy of prematurity in preterm infants.

Injection (per ml) 10mg

• Lucentis (Novartis) originator