Active ingredients: Ranibizumab
Lucentis 10 mg / ml solution for injection
Lucentis package inserts are available for pack sizes:- Lucentis 10 mg / ml solution for injection
- Lucentis 10 mg / ml solution for injection in pre-filled syringe
Indications Why is Lucentis used? What is it for?
What is Lucentis
Lucentis is a solution that is to be injected into the eye. Lucentis is one of a group of medicines called antineovascular agents. It contains an active substance called ranibizumab.
What is Lucentis for
Lucentis is used in adults to treat various eye conditions that cause decreased vision.
These conditions result from damage to the retina (the light-sensitive layer at the back of the eye) caused by:
- Growth of abnormal blood vessels that let out fluids (choroidal neovascularization, CNV). This is seen in conditions such as age-related macular degeneration (AMD) or pathological myopia (PM).
- Macular edema (swelling in the center of the retina). This swelling can be caused by diabetes (a condition called diabetic macular edema (DME)) or by blockage of the retinal veins (a condition called retinal vein occlusion (RVO)).
How Lucentis works
Lucentis specifically recognizes and binds a protein called human endothelial vascular growth factor A (VEGF-A) present in the eye. When in excess, VEGF-A causes abnormal blood vessel growth and swelling in the eye which can lead to a decrease in blood vessels. of vision in conditions such as AMD, PM, DME or RVO. By binding VEGF-A, Lucentis can block its action and prevent abnormal growth and swelling.
In these conditions, Lucentis can help stabilize and in many cases improve vision.
Contraindications When Lucentis should not be used
You must not receive Lucentis
- if you are allergic to ranibizumab or any of the other ingredients of this medicine
- if you have an "infection in one eye or the surrounding area.
- if you have pain or redness (severe intraocular inflammation) in one eye.
Precautions for use What you need to know before taking Lucentis
Talk to your doctor before receiving Lucentis.
- Lucentis is given as an "injection into" the eye. Occasionally, an "infection in the inner part of the eye", pain or redness (inflammation) detachment or rupture of one of the layers in the back of the eye (retinal detachment or rupture and detachment or rupture of the epithelium) may occur after treatment with Lucentis. retinal pigment), or clouding of the lens (cataract). It is important to identify and treat a "retinal infection or detachment as soon as possible. Tell your doctor immediately if you experience any signs such as eye pain or increased discomfort, worsening red eye", blurred or decreased vision, an increase in of corpuscles in vision or increased sensitivity to light.
- In some patients, pressure in the eye may increase for a short time immediately after the injection. This event is something you may not notice, so your doctor should check after each injection.
- Tell your doctor if you have had previous eye problems or treatments, or if you have had a stroke or signs of transient ischemic attacks (weakness or paralysis of the limbs or face, difficulty in speaking or understanding). This information will be considered when evaluating whether Lucentis is the appropriate treatment for you.
Children and adolescents (under 18 years of age)
The use of Lucentis in children and adolescents has not been studied and is therefore not recommended.
Interactions Which drugs or foods may change the effect of Lucentis
Tell your doctor if you are using, have recently used or might use any other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
- Women of childbearing potential should be advised to use effective contraception during treatment.
- There is no experience with the use of Lucentis in pregnant women, therefore the potential risks are not known. If you are pregnant, suspect or are planning to become pregnant, please discuss this with your doctor before treatment with Lucentis.
- The use of Lucentis during breastfeeding is not recommended as it is not known whether Lucentis is excreted in human milk. Ask your doctor or pharmacist for advice before treatment with Lucentis.
Driving and using machines
Temporary blurring of vision may occur after treatment with Lucentis. If this happens, do not drive or use machines until this condition has resolved.
Dose, Method and Time of Administration How to use Lucentis: Posology
How Lucentis will be given to you
Lucentis is given by your ophthalmologist as a single injection into the eye under local anesthesia. The usual dose of one injection is 0.05 ml (which contains 0.5 mg of the active ingredient). The interval between two doses injected into the same eye should be at least four weeks. All injections will be given to you by your eye doctor.
Before the injection, your doctor will clean your eye thoroughly to prevent an infection. Your doctor will also give you a local anesthetic to reduce or prevent any pain that may arise with the injection.
Treatment began with one injection of Lucentis per month. The doctor will monitor the condition of the eye and, based on the response to treatment, will decide if and when further treatment is needed.
Detailed instructions for the user can be found at the end of this leaflet under "How to prepare and administer Lucentis".
Elderly patients (65 years of age and over)
Lucentis can be used for patients 65 years of age and older without dose adjustments.
If you miss a dose of Lucentis
Contact your doctor or hospital as soon as possible to reschedule your appointment.
Before stopping Lucentis treatment
If you are considering stopping Lucentis treatment, please go to your next visit and discuss this with your doctor. Your doctor will advise you and decide how long you will need to be treated with Lucentis.
If you have any further questions on the use of this medicine, ask your doctor.
Side Effects What are the side effects of Lucentis
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The side effects associated with the administration of Lucentis are due to both the medicine itself and the injection procedure and mostly affect the eye.
The most serious side effects are described below:
Common serious side effects (may affect up to 1 in 10 patients): detachment or tear in the back of the eye (retinal detachment or rupture), manifested by flashes of light with floaters up to a temporary reduction in vision , or clouding of the lens (cataract). Uncommon serious side effects (may affect up to 1 in 100 patients): blindness, infection of the eyeball (endophthalmitis) with inflammation inside the eye.
The symptoms you may experience are described in section 2 of this leaflet (please read section 2 "What you need to know before you are given Lucentis"). Contact your doctor immediately if any of these side effects occur.
The most frequently reported side effects are described below:
Very common side effects (may affect more than 1 in 10 patients)
Visual side effects include: inflammation of the eye, haemorrhage in the back of the eye (retinal haemorrhage), visual disturbances, eye pain, particles or spots in vision (floaters), localized eye redness, eye irritation, body sensation foreign matter in the eye, increased tear production, inflammation or infection of the eyelid margin, dry eye, red or itchy eye and increased pressure in the eye.
Non-visual side effects include: sore throat, nasal congestion, runny nose, headache and joint pain.
Other side effects that may occur following treatment with Lucentis are described below:
Common side effects
Visual side effects include: decreased visual acuity, swelling of part of the eye (uvea, cornea), inflammation of the cornea (front of the eye), small marks on the surface of the eye, blurred vision, bleeding at the site injection, bleeding in the eye, itchy discharge from the eye, redness and swelling (conjunctivitis), sensitivity to light, eye discomfort, eyelid swelling, eyelid pain. Non-visual side effects include: urinary tract infection, decreased red blood cells (with symptoms such as tiredness, breathlessness, dizziness, paleness), anxiety, cough, nausea, allergic reactions such as rash, hives, itching and redness of the skin.
Uncommon side effects
Visual side effects include: inflammation and bleeding in the front of the eye, collection of pus in the eye, changes in the central part of the ocular surface, pain or irritation at the injection site, abnormal sensation in the eye, eyelid irritation.
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP and after EXP. The expiry date refers to the last day of that month.
- Store in the refrigerator (2? C - 8? C). Do not freeze.
- Keep the vial in the outer carton to protect the medicine from light.
- Do not use a package that is damaged.
Contents of the pack and other information
What Lucentis contains
- The active substance is ranibizumab (10 mg / ml). Each ml contains 10 mg of ranibizumab.
- The other ingredients are α, α-trehalose dihydrate; histidine hydrochloride, monohydrate; histidine; polysorbate 20; water for injections.
Description of what Lucentis looks like and contents of the pack
Lucentis is a solution for injection in a vial (0.23 ml). The solution is aqueous, clear, colorless to pale yellow.
Lucentis is supplied in a pack containing a glass vial of ranibizumab with a chlorobutyl rubber stopper, a blunt filter needle (18G x 1½ ″, 1.2 mm x 40 mm, 5 micrometers) for withdrawal of the vial contents, a injection needle (30G x ½ ″, 0.3mm x 13mm) and a syringe (1ml) for withdrawing the contents of the vial for intravitreal injection. All components are for single use only.
The following information is intended for healthcare professionals only: Please also refer to the section "How Lucentis will be given to you".
How to prepare and administer Lucentis
Single-use vials for intravitreal use only Lucentis should be administered by a qualified ophthalmologist experienced in intravitreal injections.
In wet AMD, visual impairment due to DME, macular edema secondary to RVO or CNV secondary to PM, the recommended dose of Lucentis is 0.5 mg in a single intravitreal injection.
This corresponds to an injected volume of 0.05 ml. The interval between two doses injected into the same eye should be at least four weeks.
Treatment is started with one injection per month until maximum visual acuity is achieved and / or there are no signs of disease activity such as changes in visual acuity and changes in other signs and symptoms of the disease during continued treatment. patients with wet AMD, DME and RVO, it may be necessary to initiate therapy with three or more consecutive monthly injections.
Therefore, monitoring and treatment intervals should be decided by the physician and should be based on disease activity, as ascertained by assessment of visual acuity and / or anatomical parameters.
If, in the physician's opinion, visual acuity and anatomical parameters indicate that the patient is not benefiting from continued treatment, Lucentis should be discontinued.
Monitoring of disease activity may include clinical examination, functional assessments, or imaging techniques (such as optical coherence tomography or fluorescein angiography).
If patients are being treated according to a treat-and-extend regimen, upon reaching maximum visual acuity and / or in the absence of signs of disease activity, treatment intervals may be gradually extended until signs of the disease or there is a deterioration in visual function. The treatment interval should be gradually extended by a maximum of two weeks in patients with wet AMD and may be extended up to one month in patients with DME. The treatment intervals may also be gradually extended in the treatment of RVO as well, however not there is sufficient data to establish the duration of these intervals. Upon re-emergence of disease activity, the treatment interval should be shortened accordingly.
In the treatment of visual impairment caused by CNV secondary to PM, many patients require only one or two injections during the first year, while some require more frequent treatment.
Lucentis and laser photocoagulation in DME and macular edema secondary to BRVO
There is some experience of Lucentis administered concurrently with laser photocoagulation. When used on the same day, Lucentis should be administered at least 30 minutes after laser photocoagulation. Lucentis can be administered to patients who have previously received laser photocoagulation.
Lucentis and photodynamic therapy with Visudyne in CNV secondary to PM
There is no experience with the administration of Lucentis in combination with Visudyne. Before administration Lucentis should be visually checked for the presence of particles and discolouration.
The injection procedure should be performed under aseptic conditions, which include surgical hand disinfection, sterile gloves, a sterile drape and sterile blepharostat (or equivalent), and the ability to perform a sterile paracentesis (if needed). performing the intravitreal procedure, the patient's history should be carefully evaluated for hypersensitivity reactions. Adequate anesthesia and a broad spectrum topical antimicrobial should be administered prior to injection to disinfect the periocular, ocular and eyelid surface, as per clinical practice.
To prepare Lucentis for intravitreal injection, please follow the instructions below:
All components are sterile and for single use only. Any component with packaging showing signs of damage or tampering must not be used. Sterility cannot be guaranteed if the component packaging seal is not intact.
- Disinfect the outside of the rubber stopper of the vial before collection.
- Aseptically attach the 5 µm filter needle (18G x 1½ ″, 1.2 mm x 40 mm, 5 µm, supplied) to a 1 ml syringe (supplied). Insert the blunt filter needle into the center of the cap until it touches the bottom of the vial.
- Withdraw all the liquid from the vial by holding it in an upright position, slightly inclined to facilitate complete withdrawal.
- Make sure that the plunger of the syringe is pulled back sufficiently when emptying the vial to completely empty the filter needle.
- Leave the filter needle blunt in the vial and remove the syringe from it. Discard the filter needle after withdrawing the contents of the vial and do not use it for intravitreal injection.
- Firmly and aseptically mount the injection needle (30G x ½ ″, 0.3mm x 13mm, supplied) onto the syringe.
- Carefully remove the cap from the injection needle without disconnecting the injection needle from the syringe. Note: Hold the yellow base of the injection needle while removing the cap.
- Carefully expel the air from the syringe and adjust the dose to 0.05 ml marked on the syringe. The syringe is ready for injection. Note: Do not clean the injection needle. Do not pull the plunger back. Insert the injection needle 3.5-4.0mm posterior to the limbus, into the vitreous chamber, avoiding the horizontal meridian and directing the needle towards the center of the globe. Inject the injection volume of 0.05 ml; change the scleral site for subsequent injections. After the injection, do not cover the needle or detach it from the syringe. Dispose of the used syringe together with the needle in an appropriate container or in accordance with local requirements.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LUCENTIS 10 MG / ML SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml contains 10 mg of ranibizumab *. Each vial contains 2.3 mg of ranibizumab in 0.23 ml of solution.
* Ranibizumab is a humanized monoclonal antibody fragment produced in the cells of Escherichia coli by recombinant DNA technology.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution
Clear, colorless to pale yellow aqueous solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Lucentis is indicated in adults for:
• Treatment of age-related neovascular (wet) macular degeneration (AMD)
• Treatment of visual impairment caused by diabetic macular edema (DME)
• The treatment of visual impairment caused by "macular edema secondary to retinal vein occlusion (branch RVO or central RVO)
• Treatment of visual impairment caused by choroidal neovascularization (CNV) secondary to pathological myopia (PM)
04.2 Posology and method of administration
Lucentis should be administered by a qualified ophthalmologist experienced in intravitreal injections.
Posology for the treatment of wet AMD
The recommended dose of Lucentis is 0.5 mg administered monthly as a single intravitreal injection. This corresponds to an injected volume of 0.05 ml.
Treatment is administered monthly and continued until maximum visual acuity is achieved ie patient visual acuity is stable for three consecutive monthly checks performed during ranibizumab treatment.
Therefore, patients' visual acuity should be monitored monthly.
Treatment should be resumed when monitoring indicates a decrease in visual acuity due to wet AMD. Monthly injections should then be administered until stable visual acuity is achieved again for three consecutive monthly checks (this implies a minimum of two injections). The interval between two doses should not be less than one month.
Posology for the treatment of visual impairment caused by DME or macular edema secondary to RVO
The recommended dose of Lucentis is 0.5 mg administered monthly as a single intravitreal injection. This corresponds to an injected volume of 0.05 ml.
Treatment is administered monthly and continued until maximum visual acuity is achieved ie patient visual acuity is stable for three consecutive monthly checks performed during ranibizumab treatment. If there is no improvement in visual acuity during the period of the first three injections, continuation of treatment is not recommended.
Therefore, patients' visual acuity should be monitored monthly.
Treatment should be resumed when monitoring indicates decreased visual acuity due to DME or macular edema secondary to RVO. Monthly injections should then be administered until stable visual acuity is achieved again for three monthly checks. consecutive (this involves a minimum of two injections). The interval between the two doses should not be less than one month.
Lucentis and laser photocoagulation in DME and macular edema secondary to BRVO
There is some experience of the administration of Lucentis concomitantly with laser photocoagulation (see section 5.1). When given on the same day, Lucentis should be given at least 30 minutes after laser photocoagulation. Lucentis can be given to patients who have previously received laser photocoagulation.
Posology for the treatment of visual impairment caused by CNV secondary to PM
Treatment should be started with a single injection.
If monitoring reveals signs of disease activity, such as reduced visual acuity and / or signs of injury, further treatment is recommended.
Disease monitoring may include a clinical examination, optical coherence tomography (OCT), or fluorescein angiography (FA).
While some patients may only need one or two injections during the first year of treatment, some may need more frequent treatment (see section 5.1). Monthly monitoring is therefore recommended for the first two months and at least every three months during the first year of treatment. After the first year, the frequency of monitoring can be determined by the doctor.
The interval between two doses should not be less than one month.
Lucentis and photodynamic therapy with Visudyne in CNV secondary to PM
There is no experience with the administration of Lucentis in combination with Visudyne.
Special populations
Hepatic insufficiency
Lucentis has not been studied in patients with hepatic insufficiency. However, no special considerations are needed for this polation.
Kidney failure
No dose adjustment is necessary in patients with renal insufficiency (see section 5.2).
Senior citizens
No dose adjustment is required in the elderly. There is "limited" experience in patients with DME over the age of 75.
Pediatric population
The safety and efficacy of Lucentis in children and adolescents below 18 years of age have not been established. There are no data available.
Method of administration
Single use vials for intravitreal use only.
Before administration Lucentis should be visually checked for the presence of particles and discolouration.
The procedure for the injection must be performed under aseptic conditions, which include disinfection of the hands as for any surgical procedure, sterile gloves, a sterile drape and a sterile blepharostat (or equivalent) and the possibility of performing a sterile paracentesis (if necessary The patient's history of hypersensitivity reactions should be carefully evaluated prior to the intravitreal procedure (see section 4.4). Adequate anesthesia and a broad spectrum topical antimicrobial should be administered prior to injection to disinfect the periocular, ocular and eyelid surface, as per clinical practice.
For information on the preparation of Lucentis, see section 6.6.
Insert the injection needle 3.5-4.0 mm posterior to the limbus, into the vitreous chamber, avoiding the horizontal meridian and directing the needle towards the center of the eyeball. Inject the injection volume of 0.05 ml; change the scleral site for subsequent injections.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with current or suspected ocular or periocular infections.
Patients with ongoing severe intraocular inflammation.
04.4 Special warnings and appropriate precautions for use
Reactions related to intravitreal injection
Intravitreal injections, including those with Lucentis, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal rupture and iatrogenic traumatic cataract (see section 4.8). Suitable aseptic injection techniques should always be used for the administration of Lucentis. In addition, patients should be monitored in the week following the injection to allow for rapid treatment in the event of an infection. Patients should be instructed on how to report any symptoms suggestive of endophthalmitis or any of the above events without delay.
Increases in intraocular pressure
Transient increases in intraocular pressure (IOP) have been observed within 60 minutes of Lucentis injection. Prolonged increases in IOP have also been observed (see section 4.8). Intraocular pressure and optic nerve head perfusion should be monitored and treated appropriately.
Bilateral treatment
Limited data on bilateral use of Lucentis (including same-day dosing) do not indicate an increased risk of systemic adverse events compared with unilateral treatment.
Immunogenicity
There is a potential for immunogenicity with Lucentis. As there is a possibility of increased systemic exposure in subjects with DME, an increased risk of developing hypersensitivity in this patient population cannot be excluded. Patients should also be educated on how to report if intraocular inflammation worsens because it could be a clinical symptom attributable to the formation of intraocular antibodies.
Concomitant use with other anti-VEGFs (vascular endothelial growth factor)
Lucentis must not be administered concomitantly with other anti-VEGF medicinal products (systemic or ocular).
Lucentis discontinuation
The dose should not be administered and treatment should not be resumed before the next scheduled treatment in the case of:
• a decrease in best corrected visual acuity (BCVA) ≥30 letters compared to the last evaluation;
• an intraocular pressure ≥30 mmHg;
• a retinal break;
• a "subretinal haemorrhage extending to the center of the fovea, or if the extent of the haemorrhage is ≥50% of the total lesion area";
• intraocular surgery performed or planned within the previous or next 28 days.
Rupture of the retinal pigment epithelium
Risk factors associated with the onset of retinal pigment epithelial rupture following anti-VEGF therapy for wet AMD include large and / or high retinal pigment epithelial detachment.When initiating therapy with Lucentis, caution should be exercised in patients with these risk factors for rupture of the retinal pigment epithelium.
Regmatogenous retinal detachment or macular holes
Treatment should be discontinued in individuals with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.
Populations with limited data
There is only limited experience in the treatment of subjects with DME secondary to type I diabetes. Lucentis has not been studied in patients who had previously received intravitreal injections, in patients with active systemic infections, proliferative diabetic retinopathy, or in patients with concomitant medical conditions. ocular such as retinal detachment or macular hole. There is also no experience on treatment with Lucentis in diabetic patients with HbAlc greater than 12% and uncontrolled hypertension. Lack of information should be considered by the physician when treating these patients.
In PM patients, there are limited data on the effect of Lucentis in patients previously treated with unsuccessful photodynamic therapy with verteporfin (vPDT). Furthermore, while a consistent effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficient data on the effect of Lucentis in PM subjects with extrafoveal lesions.
Systemic effects following intravitreal administration
Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors.
There are limited data on the safety of treatment of DME, macular edema caused by RVO and CNV secondary to PM in patients with a history of stroke or transient ischemic attacks. Particular caution should be exercised when treating such patients (see section 4.8).
Previous episodes of RVO, ischemic branch and central RVO
There is limited experience in the treatment of patients with previous episodes of RVO and patients with ischemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO who present with loss of visual function with clinical signs of irreversible ischaemia, treatment is not recommended.
04.5 Interactions with other medicinal products and other forms of interaction
No conventional interaction studies have been performed.
For the combined use of photodynamic therapy (PDT) with verteporfin and Lucentis in wet AMD and PM, see section 5.1.
For the combined use of laser photocoagulation and Lucentis in the treatment of DME and BRVO, see sections 4.2 and 5.1.
04.6 Pregnancy and lactation
Women of childbearing potential / contraception in women
Women of childbearing potential should use effective contraception during treatment.
Pregnancy
For ranibizumab, no clinical data on exposed pregnancies are available. Studies in cynomolgus monkeys have shown no direct or indirect harmful effects with respect to pregnancy or embryonal / fetal development (see section 5.3). Systemic exposure to ranibizumab is low following ocular administration, but due to the mechanism of action ranibizumab should be considered as potentially teratogenic and embryo / foetotoxic. Therefore, ranibizumab should not be used during pregnancy unless the expected benefits outweigh the potential risk to the fetus. Women planning to become pregnant and have been treated with ranibizumab are recommended to wait at least 3 months after their last dose of ranibizumab before conceiving a baby.
Pregnancy
It is not known whether Lucentis is excreted in human milk. It is recommended not to breastfeed while using Lucentis.
Fertility
There are no data available on fertility.
04.7 Effects on ability to drive and use machines
The Lucentis treatment procedure may induce transient visual disturbances which may affect the ability to drive or use machines (see section 4.8). Patients experiencing these symptoms should not drive or operate machinery until these transient visual disturbances cease.
04.8 Undesirable effects
Summary of the safety profile
Most adverse reactions reported following administration of Lucentis are related to the intravitreal injection procedure.
The most frequently reported ocular adverse reactions following Lucentis injection are: eye pain, ocular hyperaemia, increased intraocular pressure, vitreitis, vitreous detachment, retinal haemorrhage, visual disturbance, floaters (vitreous floaters), conjunctival haemorrhage, irritation eye, foreign body sensation in the eye, increased tearing, blepharitis, dry eye and itchy eye.
The most frequently reported non-ocular adverse reactions are headache, nasopharyngitis and arthralgia.
Less frequently reported but more serious adverse reactions include endophthalmitis, blindness, retinal detachment, retinal rupture and iatrogenic traumatic cataract (see section 4.4).
Patients should be informed of the symptoms of these potential adverse reactions and instructed to inform their physician if they experience signs such as eye pain or increased discomfort, worsening of eye redness, blurred or decreased vision, an increased number of vitreous floaters, or an "increased sensitivity to light.
Adverse reactions reported following administration of Lucentis in clinical studies are summarized in the table below.
Adverse Reaction Table #
Adverse reactions are listed by system organ class and frequency using the following convention: very common (≥1 / 10), common (≥1 / 100,
Infections and infestations
Very common Nasopharyngitis
common Urinary tract infection *
Disorders of the blood and lymphatic system
common Anemia
Disorders of the immune system
common Hypersensitivity
Psychiatric disorders
common Anxiety
Nervous system disorders
Very common Headache
Eye disorders
Very common Vitreitis, vitreous detachment, retinal haemorrhage, visual disturbances, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in the eye, increased lacrimation, blepharitis, dry eye, ocular hyperaemia, itchy eye.
common Retinal degeneration, retinal disorders, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, tear of the retinal pigment epithelium, impaired visual acuity, vitreous haemorrhage, vitreous disturbances, uveitis, iritis, iridocyclitis, cataract, subcapsular cataract posterior capsule, punctate keratitis, corneal abrasion, anterior chamber reaction, blurred vision, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis
allergic, ocular discharge, luminous flashes, photophobia, ocular discomfort, eyelid edema, eyelid pain, conjunctival hyperaemia.
Uncommon Blindness, endophthalmitis, hypopion, hyphema, keratopathy, iris synechiae, corneal deposits, corneal edema, corneal striae, injection site pain, injection site irritation, abnormal sensation in the eye, eyelid irritation.
Respiratory, thoracic and mediastinal disorders
common Cough
Gastrointestinal disorders
common Nausea
Skin and subcutaneous tissue disorders
common Allergic reactions (rash, hives, itching, erythema)
Musculoskeletal and connective tissue disorders
Very common Arthralgia
Diagnostic tests
Very common Increased intraocular pressure
# Adverse reactions were defined as adverse events (in at least 0.5 percentage points of patients) that occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with Lucentis 0.5 mg compared to those who received control treatment (sham or PDT verteporfin).
* observed only in the population with DME
Adverse reactions related to drug category
In the phase III wet AMD studies, the overall frequency of non-ocular haemorrhages, an adverse event potentially related to VEGF inhibitors (endothelial vessel growth factor), was slightly increased in patients treated with ranibizumab. However, there is not. was a consistent pattern between the different hemorrhages. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, resulting from the intravitreal use of VEGF inhibitors. A low incidence of arterial thromboembolic events was observed in clinical trials with Lucentis in patients with AMD, DME, RVO and PM and no differences were observed between the ranibizumab groups compared to control.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Cases of accidental overdose have been reported from clinical trials in wet AMD and post-marketing data. The adverse reactions most frequently associated with these cases were increased intraocular pressure, transient blindness, decreased visual acuity, corneal edema and pain. If an overdose occurs, intraocular pressure should be monitored and treated as deemed necessary by the physician.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, anti-neovascular agents, ATC code: S01LA04
Ranibizumab is a humanized recombinant monoclonal antibody fragment directed against human vascular endothelial growth factor A (VEGF-A). It binds with a high affinity to VEGF-A isoforms (eg VEGF110, VEGF121 and VEGF165), thus preventing the binding of VEGF-A to its VEGFR-1 and VEGFR-2 receptors. to its receptors leads to a proliferation of endothelial cells to a neovascularization, and to an increase in vascular permeability, which are thought to contribute to the progression of the neovascular form of age-related macular degeneration, pathological myopia or decreased vision caused by either diabetic macular edema or "Macular edema secondary to RVO.
Treatment of wet AMD
For wet AMD, the safety and clinical efficacy of Lucentis were evaluated in three 24-month randomized, double-blind, sham- or active-controlled studies in patients with neovascular AMD. A total of 1,323 patients (879 treated and 444 controls) were enrolled in these studies.
In study FVF2598g (MARINA), 716 patients with minimally classical or occult choroidal neovascularization (CNV) lesions without classical component received monthly intravitreal injections of Lucentis 0.3 mg (n = 238) or 0.5 mg (n = 240) or sham injections (n = 238).
In study FVF2587g (ANCHOR), 423 patients with predominantly classical CNV received one of the following treatments: 1) monthly intravitreal injections of Lucentis 0.3 mg and PDT sham (n = 140); 2) monthly intravitreal injections of Lucentis 0.5 mg and PDT sham (n = 140); or 3) intravitreal sham injections and PDT with verteporfin (n = 143). PDT with verteporfin or sham was administered together with the initial injection of Lucentis and subsequently every 3 months if fluorangiography showed persistence or resumption of vascular leakage.
The key findings are summarized in Tables 1, 2 and Figure 1.
Table 1 Results at month 12 and month 24 in study FVF2598g (MARINA)
ap
Table 2 Results at Month 12 and Month 24 in Study FVF2587g (ANCHOR)
Table
The results of both studies showed that continued treatment with ranibizumab could also be of benefit in patients who lost ≥15 letters of best corrected visual acuity (BCVA) in the first year of treatment.
Study FVF3192g (PIER) was a randomized, double-blind, sham-controlled study designed to evaluate the safety and efficacy of Lucentis in 184 patients with all forms of neovascular AMD. Patients received intravitreal injections of Lucentis 0.3 mg (n = 60) or 0.5 mg (n = 61) or sham injections (n = 63) once monthly for 3 consecutive doses, followed by one dose given once every 3 months. From month 14 of the study, patients treated with a sham injection were admitted to treatment with ranibizumab and from month 19, more frequent treatments could be performed. Patients treated with Lucentis in the PIER study received an average of 10 treatments in total.
The primary efficacy endpoint was the mean change in visual acuity at 12 months compared to baseline. After an initial increase in visual acuity (following monthly dose), on average, patients' visual acuity decreased with quarterly dosing, returning to baseline at month 12 and this effect was maintained in the majority of treated patients. with ranibizumab (82%) at Month 24. Data from a limited number of subjects who had been transferred to ranibizumab treatment after more than one year of sham treatment suggested that early treatment initiation may be associated with better retention of "visual acuity.
In both the MARINA and ANCHOR studies, the improvement in visual acuity observed with Lucentis 0.5 mg at 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) score. differences between Lucentis 0.5 mg and the two control groups were evaluated with p values ranging from 0.009 to
The efficacy of Lucentis in treating wet AMD was confirmed in post-marketing AMD studies. Data from two studies (MONT BLANC, BPD952A2308 and DENALI, BPD952A2309) did not demonstrate additional effects. of the combined administration of verteporfin (Visudyne PDT) and Lucentis compared to Lucentis alone.
Treatment of visual impairment due to DME
The safety and efficacy of Lucentis were evaluated in two randomized, double-blind, sham-controlled or active 12-month studies in patients with decreased vision due to diabetic macular edema. A total of these studies were enrolled. of 496 patients (336 active and 160 controls), most had type II diabetes, 28 treated patients had type I diabetes.
In phase II of study D2201 (RESOLVE), 151 patients were treated with ranibizumab (6 mg / ml, n = 51, 10 mg / ml, n = 51) or sham (n = 49) with one "intravitreal injection per month. until predefined criteria were met. The starting dose of ranibizumab (0.3 mg or 0.5 mg) could be doubled at any time during the study after the first injection. Laser photocoagulation was allowed as a rescue treatment from month 3 into both treatment arms.The study had two parts: an exploratory part (the first 42 patients visited at month 6) and a confirmatory part (the remaining 109 patients visited at month 12).
Key findings from the confirmatory part of the study (2/3 of patients) are summarized in Table 3.
Table 3 Outcomes at Month 12 in Study D2201 (RESOLVE) (Total Study Population)
ap
In phase III study D2301 (RESTORE), 345 patients with visual impairment due to macular edema were randomized to receive either an "intravitreal injection of 0.5 mg ranibizumab as monotherapy and laser sham photocoagulation (n = 116), or a combination of 0.5 mg ranibizumab and laser photocoagulation (n = 118) or a sham injection and laser photocoagulation (n = 111). Treatment with ranibizumab was initiated with monthly intravitreal injections and continued until visual acuity remained stable for at least three consecutive monthly checks. Treatment was resumed when a reduction in BCVA due to DME progression was observed. Laser photocoagulation was administered at baseline on the same day, at least 30 minutes prior to ranibizumab injection, and thereafter as needed based on ETDRS criteria.
The key findings are summarized in Table 4 and Figure 2.
Table 4 Results at Month 12 in Study D2301 (RESTORE)
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The effect was consistent in most subgroups. However, subjects with a fairly high BCVA at baseline (> 73 letters) with macular edema and central retinal thickness
The improvement in visual acuity at Month 12 observed with Lucentis 0.5 mg was accompanied by patient-reported benefits of major vision-related functions as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) score. subclasses of this questionnaire, differences due to treatment cannot be established.The difference between Lucentis 0.5 mg and the control group was evaluated with a p-value of 0.0137 (ranibizumab mono) and 0.0041 (ranibizumab + laser) for the VFQ-25 composite score.
In both studies, the visual improvement was accompanied by a continuous reduction in macular edema measured as central retinal thickness (CRT).
Treatment of visual impairment caused by macular edema secondary to RVO
The clinical safety and efficacy of Lucentis in patients with visual impairment due to macular edema secondary to RVO were evaluated in randomized, double-blind, controlled trials: BRAVO and CRUISE which recruited patients with BRVO (n = 397) and CRVO ( n = 392). In both studies, patients received either 0.3 mg or 0.5 mg ranibizumab intravitreal or sham injections. After 6 months, patients in the sham control arm were moved to the ranibizumab group 0.5 mg. In the BRAVO study, laser photocoagulation as a rescue treatment was allowed in all arms from month 3.
Key findings from the BRAVO and CRUISE studies are presented in Tables 5 and 6
Table 5 Results at month 6 and 12 (BRAVO)
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Table 6 Results at Month 6 and 12 (CRUISE)
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In both studies, the visual improvement was accompanied by a continuous and significant reduction in macular edema measured in terms of central retinal thickness.
In BRVO patients (BRAVO study and HORIZON study extension): After 2 years, patients who had been treated with sham injections in the first 6 months and subsequently switched to ranibizumab treatment had a gain in AV (& symp; 15 letters) comparable to that of patients who had been treated with ranibizumab since study initiation (& symp; 16 letters). However, the number of patients completing 2 years was limited and only quarterly visits were scheduled in the HORIZON study. there is sufficient evidence to conclude with recommendations on when ranibizumab treatment should be initiated in patients with BRVO.
In CRVO patients (CRUISE study and HORIZON study extension): After 2 years, patients who had been treated in the first 6 months with sham injections and subsequently transferred to ranibizumab treatment showed no gains in AV (& symp; 6 letters) compared with those of patients who had been treated with ranibizumab since study initiation (& symp; 12 letters).
The improvement in visual acuity observed with ranibizumab treatment at months 6 and 12 was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) subgroup of near and distant activities. The difference between Lucentis 0.5 mg and the control group was found to be between p values between 0.02 and 0.0002.
Treatment of visual impairment due to CNV secondary to PM
The safety and clinical efficacy of Lucentis in patients with visual impairment due to CNV in PM were validated based on 12-month data from the pivotal randomized, double-blind, controlled study F2301 (RADIANCE). This study aimed to evaluate Two different dosing regimens of ranibizumab 0.5 mg administered by intravitreal injection versus verteporfin PDT (vPDT, Visudyne photodynamic therapy). The 277 patients were randomized to one of the following arms:
• Group I (ranibizumab 0.5 mg, treatment regimen determined by "stability" criteria defined as no change in BCVA compared to the previous two months' assessments).
• Group II (ranibizumab 0.5 mg, treatment regimen determined by "disease activity" criteria defined as visual impairment attributable to intra- or subretinal fluid or active leakage caused by CNV lesions as evidenced by OCT and / or AF) .
• Group III (patients treated with vPDT - with the possibility of treatment with ranibizumab starting from month 3).
During the 12 months of the study, patients received an average of 4.6 injections (range 1-11) in Group I and 3.5 injections (range 1-12) in Group II. Among patients belonging to Group II, which reflects the recommended posology (see section 4.2), 50.9% of patients underwent treatment with 1 to 2 injections, 34.5% 3 to 5 injections and 14.7% gave 6 to 12 injections over the 12-month study. 62.9% of Group II patients required no injections during the second 6 months of the study.
Key findings from RADIANCE are summarized in Table 7 and Figure 5.
Table 7 Results at Month 3 and 12 (RADIANCE)
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b Comparative control up to month 3. Patients randomized to receive vPDT were eligible for ranibizumab treatment at month 3 (in Group III, 38 patients received ranibizumab at month 3)
The improvement in vision was accompanied by a reduction in central retinal thickness.
Compared to the vPDT-treated group, patients in the ranibizumab-treated groups reported benefit (p-value
Pediatric population
The safety and efficacy of ranibizumab in children have not yet been established.
The European Medicines Agency has waived the obligation to submit the results of studies with Lucentis in all subsets of the pediatric population for neovascular AMD, visual impairment due to DME, visual impairment due to secondary macular edema to RVO and visual impairment due to CNV secondary to PM (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Following monthly intravitreal administration of Lucentis to patients with neovascular AMD, serum concentrations of ranibizumab were generally low, with peak levels (Cmax) generally below the ranibizumab concentration needed to inhibit the biological activity of VEGF by 50% (11- 27 ng / mL, evaluated in a test in vitro cell proliferation). Cmax was dose proportional throughout the dose range of 0.05 to 1.0 mg / eye. In a limited number of patients with DME, the detected serum concentrations indicate that a slightly higher systemic exposure cannot be excluded than to those observed in patients with neovascular AMD. The serum concentrations of ranibizumab in patients with RVO were similar or slightly higher than those observed in patients with neovascular AMD.
Based on population pharmacokinetic analysis and serum clearance of ranibizumab for neovascular AMD patients treated with the 0.5 mg dose, the mean vitreous elimination half-life of ranibizumab is approximately 9 days. At the time of monthly intravitreal administration of Lucentis 0.5 mg / eye, the serum C of ranibizumab, reached approximately 1 day post dose, is expected to generally range between 0.79 and 2.90 ng / ml, while it is expected that the Cmin generally fluctuates between 0.07 and 0.49 ng / ml. Serum concentrations of ranibizumab are estimated to be approximately 90,000-fold lower than vitreous concentrations.
Patients with renal insufficiency: No conventional studies have been performed to examine the pharmacokinetics of Lucentis in patients with renal insufficiency. In a "pharmacokinetic analysis in a population of neovascular AMD patients, 68% (136 of 200) of the patients had" renal insufficiency (46.5% mild [50-80 mL / min], 20% moderate [30 -50 mL / min] and 15% severe [systemic clearance was slightly lower, but this was not clinically significant.
Patients with hepatic insufficiency: No conventional studies have been performed to examine the pharmacokinetics of Lucentis in patients with hepatic insufficiency.
05.3 Preclinical safety data
Bilateral intravitreal administration of ranibizumab to cynomolgus monkeys at doses between 0.25 mg / eye and 2.0 mg / eye once every 2 weeks for up to 26 weeks resulted in dose-dependent ocular effects.
Intraocularly, dose-dependent increases in flare and cells occurred in the anterior chamber, peaking 2 days after injection. The severity of the inflammatory response generally decreases with subsequent injections or during the recovery period. In the posterior segment Cellular infiltrations and vitreous floaters occurred, which also tended to be dose-dependent and generally persisted until the end of the treatment period. In the 26-week study, the severity of vitreous inflammation increased with the number of injections. However, reversibility was observed after the recovery period. The nature and duration of the posterior segment inflammation is indicative of an immune-mediated antibody response, which may be clinically irrelevant. Cataract formation has been observed in some animals after a relatively long period of intense inflammation, suggesting that changes of the lens were secondary to severe inflammation.A transient increase in intraocular pressure was observed after administration, regardless of dose, following intravitreal injections.
Microscopic ocular changes were related to inflammation and did not indicate degenerative processes. Inflammatory granulomatous changes were noted in the optic disc of some eyes. These posterior segment changes diminished, and in some cases resolved, during the recovery period.
There were no signs of systemic toxicity following intravitreal administration. Serum and vitreous antibodies to ranibizumab were found in a subset of treated animals.
No carcinogenicity or mutagenicity data are available.
In pregnant monkeys, intravitreal injection of ranibizumab resulting in a maximum systemic exposure 0.9-7 times the worst clinical exposure did not cause developmental toxicity or teratogenicity, and had no effect on weight or structure of the skin. placenta, although ranibizumab should be considered potentially teratogenic and embryo / foetotoxic based on its pharmacological effect.
The absence of mediated effects of ranibizumab on embryo / fetal development is plausibly linked mainly to the inability of the Fab fragment to cross the placenta. However, a case was described with high maternal serum levels of ranibizumab and the presence of ranibizumab in fetal serum, suggesting that the anti-ranibizumab antibody acted as a protein (containing the FC region) that transports ranibizumab, thereby decreasing its elimination from maternal serum and allowing its transfer to the placenta. Since the tests on embryo / fetal development have been conducted on healthy pregnant animals and some diseases (such as diabetes) can modify the placental permeability to a Fab fragment, the study must be interpreted with caution.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
α, α-trehalose dihydrate
Histidine hydrochloride, monohydrate
Histidine
Polysorbate 20
Water for injections
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze.
Keep the vial in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
0.23 ml sterile solution in a vial (type I glass) with a stopper (chlorobutyl rubber), 1 blunt filter needle (18G x 1½ ", 1.2 mm x 40 mm, 5 mcm), 1 injection needle ( 30G x ½ ", 0.3 mm x 13 mm) and 1 syringe (polypropylene) (1 ml). The pack contains 1 vial.
06.6 Instructions for use and handling
The vial, injection needle, filter needle and syringe are for single use only. Reuse can cause infection or other disease / injury. All components are sterile. Any component with packaging showing signs of damage or tampering must not be used. Sterility cannot be guaranteed if the component packaging seal is not intact.
To prepare Lucentis for intravitreal injection, please follow the instructions below:
1. Disinfect the outside of the rubber stopper of the vial before collection.
2. Aseptically attach the 5 mcm filter needle (18G x 1½ ", 1.2 mm x 40 mm, supplied) to a 1 ml syringe (supplied). Insert the blunt filter needle into the center of the stopper until it touches the bottom of the vial.
3. Withdraw all the liquid from the vial by holding it in an upright position, slightly tilted to facilitate complete withdrawal.
4. Make sure that the plunger of the syringe is pulled back far enough when emptying the vial to completely empty the filter needle.
5. Leave the filter needle blunt in the vial and remove the syringe from it. Discard the filter needle after withdrawing the contents of the vial and do not use it for intravitreal injection.
6. Attach the injection needle (30G x ½ ", 0.3mm x 13mm, supplied) securely and aseptically to the syringe.
7. Carefully remove the cap from the injection needle without disconnecting the injection needle from the syringe.
Note: Hold the yellow base of the injection needle while removing the cap.
8. Carefully expel the air from the syringe and adjust the dose to 0.05 ml marked on the syringe. The syringe is ready for injection.
Note: Do not clean the injection needle. Do not pull back the plunger.
After the injection, do not cover the needle or detach it from the syringe. Dispose of the used syringe together with the needle in an appropriate container or in accordance with local requirements.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/06/374/001
037608027
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 22 January 2007
Date of most recent renewal: 24 January 2012
10.0 DATE OF REVISION OF THE TEXT
05/2014
