Active ingredients: Esomeprazole
LUCEN 20 mg gastro-resistant tablets
LUCEN 40 mg gastro-resistant tablets
Lucen package inserts are available for pack sizes: - LUCEN 20 mg gastro-resistant tablets, LUCEN 40 mg gastro-resistant tablets
- LUCEN 10 mg gastro-resistant granules for oral suspension, in sachet
- LUCEN 40 mg powder for solution for injection / infusion
Indications Why is Lucen used? What is it for?
LUCEN contains a medicine called esomeprazole. It belongs to a group of medicines called 'proton pump inhibitors', which work by reducing the amount of acid produced by the stomach.
LUCEN is used for the treatment of the following disorders:
- "Gastroesophageal reflux disease" (GERD). It occurs when acid from the stomach escapes into the esophagus (the tube that connects the throat to the stomach), causing pain, inflammation and burning.
- Stomach or upper bowel ulcers infected with bacteria called "Helicobacter pylori". If you have these conditions, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.
- Stomach ulcers caused by medicines called NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). LUCEN can also be used to prevent stomach ulcers from forming while taking NSAIDs.
- Excess stomach acid caused by a tumor in the pancreas (Zollinger-Ellisson syndrome).
- Prolonged treatment of re-bleeding of ulcers, after prevention with intravenous administration of Lucen
Contraindications When Lucen should not be used
Do not take LUCEN:
- if you are allergic (hypersensitive) to esomeprazole or any of the other ingredients of this medicine (listed in section: Further information).
- if you are allergic to other proton pump inhibitor medicines (e.g. pantoprazole, lansoprazole, rabeprazole, omeprazole).
- if you are taking a medicine containing nelfinavir (used to treat HIV).
You should not take LUCEN if it falls into any of the above cases. If in doubt, consult your doctor or pharmacist before taking LUCEN.
Precautions for use What you need to know before taking Lucen
Take special care with LUCEN
Talk to your doctor or pharmacist before taking LUCEN if:
- You have severe liver problems
- You have severe kidney problems.
LUCEN can mask the symptoms of other diseases. Therefore, if any of the following happen to you before you start taking or while you are taking LUCEN, tell your doctor immediately:
- You lose a lot of weight for no reason or have trouble swallowing
- Stomach pain or indigestion occurs
- Start vomiting food or blood
- The stools are black (blood-stained stools).
If you have been prescribed LUCEN "as needed", contact your doctor if symptoms persist or change in characteristics.
If you take a proton pump inhibitor such as LUCEN, especially for longer than one year, you may have a slightly increased risk of fracture of the hip, wrist or spine. If you have osteoporosis or are taking corticosteroids (which may increase the risk of osteoporosis) consult your doctor
Interactions Which drugs or foods may change the effect of Lucen
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Indeed, LUCEN can affect the way some medicines work and some medicines can have an effect on LUCEN. You should not take LUCEN if you are taking a medicine containing nelfinavir (used to treat HIV).
Tell your doctor or pharmacist if you are taking any of the following medicines:
- Atazanavir (used to treat HIV)
- Clopidogrel (used to prevent blood clots)
- Ketoconazole, itraconazole or voriconazole (used to treat infections caused by fungi).
- Erlotinib (used to treat cancer).
- Citalopram, imipramine or clomipramine (used to treat depression).
- Diazepam (used for the treatment of anxiety, for muscle relaxation or in epilepsy).
- Phenytoin (used in epilepsy) If you are taking phenytoin, your doctor will need to monitor you when starting or stopping treatment with LUCEN.
- Medicines used to thin the blood, such as warfarin. Your doctor may monitor you when you start or stop treatment with LUCEN.
- Cilostazol (used to treat intermittent claudication - pain in the legs when walking due to insufficient blood supply).
- Cisapride (used for indigestion and heartburn).
- Digoxin (used for heart problems).
- Methotrexate (a chemotherapy drug used in high doses to treat cancer) - if you are taking high doses of methotrexate, your doctor may temporarily stop your treatment with Lucen.
- Tacrolimus (used in organ transplants)
- Rifampicin (used to treat tuberculosis).
- St. John's wort (Hypericum perforatum) (used to treat depression).
If your doctor has prescribed antibiotics such as amoxicillin and clarithromycin with LUCEN for the treatment of ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
Before taking LUCEN, tell your doctor if you are pregnant or want to become pregnant. Ask your doctor or pharmacist for advice before taking any medicine. Your doctor will decide whether you can take LUCEN during this time.
It is not known whether LUCEN passes into breast milk, so you should not take LUCEN if you are breastfeeding.
Taking LUCEN with food and drink
The tablets can be taken on a full stomach or on an empty stomach.
Driving and using machines
LUCEN is unlikely to affect your ability to drive or use any tools or machines.
Important information about some of the ingredients of LUCEN
LUCEN gastro-resistant tablets contain sucrose which is a type of sugar. If you have been told by your doctor that you have an "intolerance to some sugars, consult him before taking the medicine.
Dosage and method of use How to use Lucen: Dosage
Always take LUCEN exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist.
- LUCEN gastro-resistant tablets are not recommended for children under 12 years of age
- If you have been taking this medicine for a long time your doctor will monitor you (particularly if you have been taking the medicine for more than a year)
- If your doctor has told you to take the medicine when needed, as needed, please tell your doctor if your symptoms change.
Taking the medicine
- You can take the tablets at any time of the day.
- You can take the tablets on a full stomach or on an empty stomach.
- Swallow the tablets whole with a drink of water. Do not chew or crush the tablets as they contain coated granules which protect the drug from gastric acidity. It is therefore important not to damage the granules.
What to do if you have trouble swallowing the tablets
If you have trouble swallowing the tablets:
- Put the tablets in a glass of still water. Other liquids should not be used
- Stir until the tablets dissolve (the mixture will not have a clear appearance). Drink immediately or at least within 30 minutes. Always mix them before drinking
- To make sure that you have taken all of the medicine, rinse the glass thoroughly by filling it halfway with water and drink. The solid particles contain the medicine and should not be chewed or crushed.
If you are absolutely unable to swallow, the tablet can be mixed with some water, inserted into a syringe and administered through a tube directly into the stomach (gastric tube).
How much medication to take
- Your doctor will advise you on the number of tablets to take and for how long. This is a function of your physical condition, age and liver condition.
- Usual doses are given below.
Treatment of heartburn caused by gastroesophageal reflux disease (GERD):
Adults and children from 12 years of age:
- If your doctor has found your esophagus slightly damaged, the usual dose is one 40 mg LUCEN gastro-resistant tablet once a day for 4 weeks. Your doctor may tell you to continue the treatment, taking the same dose, for a further 4 weeks, in case the esophagus has not healed.
- After healing of the esophagus, the usual dose is one 20 mg LUCEN gastro-resistant tablet once daily.
- If the esophagus is not damaged, the usual dose is one LUCEN 20 mg gastro-resistant tablet each day. When your symptoms are under control, your doctor will inform you that you can take the medicine when needed, up to a maximum of one gastro-resistant tablet. of Lucen 20 mg per day.
- If you have severe liver problems, your doctor will give you a lower dose.
Treatment of ulcers caused by Helicobacter pylori infection and prevention of their reappearance:
- Adults from 18 years of age onwards: the usual dose is one LUCEN 20 mg gastro-resistant tablet twice a day for one week.
- Your doctor will also tell you to take antibiotics called amoxicillin and clarithromycin.
Treatment of gastric ulcers caused by NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):
- Adults from 18 years of age onwards: the usual dose is one LUCEN 20 mg gastro-resistant tablet once a day for 4 to 8 weeks.
Prevention of stomach ulcers if you are taking NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):
- Adults from 18 years of age onwards: the usual dose is one LUCEN 20 mg gastro-resistant tablet once a day.
Treatment of excess stomach acid caused by a growth in the pancreas (Zollinger-Ellison syndrome):
- Adults from 18 years of age onwards: the usual dose is one LUCEN 40 mg gastro-resistant tablet twice a day.
- Your doctor will adjust the dose according to your need and will also decide how long to continue the treatment.
The maximum dose is 80 mg twice a day.
Prolonged treatment of re-bleeding of ulcers, after prevention with intravenous administration of Lucen:
The usual dose is one Lucen 40 mg tablet once a day for 4 weeks.
Overdose What to do if you have taken too much Lucen
If you take more LUCEN than you should
If you have taken more LUCEN than prescribed by your doctor, tell your doctor or pharmacist immediately.
If you forget to take LUCEN
- If you forget to take a dose of LUCEN, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose.
- Do not take a double dose (two doses simultaneously) to make up for a forgotten dose.
Side Effects What are the side effects of Lucen
Like all medicines, LUCEN can cause side effects, although not everybody gets them.
If you notice any of the following serious side effects, stop taking LUCEN and contact your doctor immediately:
- Sudden wheezing, swelling of the lips, tongue and throat or body, rash, fainting or difficulty in swallowing (severe allergic reaction).
- Skin redness with blisters or peeling. Severe blistering and bleeding can also appear in the lips, eyes, mouth, nose and genitals. This may be "Stevens-Johnson syndrome" or "toxic epidermal necrolysis".
- Yellow skin, dark urine, and tiredness can be symptoms of liver problems. These effects are rare, affecting less than 1 in 1000 people.
Other side effects include:
Common (affects less than 1 in 10 people):
- Headache.
- Effects on the stomach or intestines: diarrhea, stomach pain, constipation, flatulence.
- Nausea or vomiting.
Uncommon (affects less than 1 in 100 people):
- Swelling in the feet and ankles.
- Disturbed sleep (insomnia).
- Dizziness, pins and needles, sleepiness.
- Dizziness.
- Dry mouth
- Changes in blood tests that check how the liver is working.
- Skin rash, hives and itching.
- Fracture of the hip, wrist or spine (if Lucen is used in high doses and for prolonged periods).
Rare (affects less than 1 in 1,000 people):
- Blood problems, such as a reduced number of white blood cells and platelets. This can cause weakness, bruising, or make infections easier.
- Low levels of sodium in the blood. This can cause weakness, vomiting and cramps.
- Feeling agitated, confused or depressed.
- Changes in taste.
- Problems with your eyesight, such as blurred vision.
- Sudden wheezing or shortness of breath (bronchospasm).
- Inflammation of the inside of the mouth.
- An infection called "thrush" which can affect the gut and is caused by a fungus.
- Liver problems, including jaundice which can cause yellow skin, dark urine and tiredness.
- Hair loss (alopecia).
- Skin rash on sun exposure.
- Joint pain (arthralgia) or muscle pain (myalgia).
- General feeling of being unwell and lack of strength.
- Increased sweating.
Very rare (affects less than 1 in 10,000 people):
- Changes in the number of blood cells, including agranulocytosis (lack of white blood cells).
- Aggression.
- Seeing, feeling or hearing things that are not there (hallucinations).
- Severe liver problems leading to liver failure and inflammation of the brain.
- Sudden onset of severe rash or blistering or peeling of the skin. This may be associated with high fever and joint pain (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).
- Muscle weakness.
- Severe kidney problems.
- Breast enlargement in men.
Not known (frequency cannot be estimated from the available data)
- If you take LUCEN for more than three months, your blood levels of magnesium may drop. Low magnesium levels can manifest themselves with fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you have any of these symptoms, please consult your doctor immediately. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor should decide whether to check your blood magnesium levels periodically.
- Inflammation in the intestine (leading to diarrhea).
LUCEN can in very rare cases affect white blood cells leading to immunodeficiency. If you have an infection with symptoms such as fever with severe deterioration of your general physical condition or fever with symptoms of local infection, such as pain in the neck, throat or mouth or difficulty urinating, you should see your doctor as soon as possible so that lack of white blood cells (agranulocytosis) can be ruled out through a blood test. It is important for you to give information about the medicines you are taking. Do not worry about the list of possible side effects above. You may not get any. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or the pharmacist.
Expiry and Retention
- Keep out of the reach and sight of children.
- Do not store above 30 ° C.
- Store in the original package (blister) or keep the container tightly closed (bottle) in order to protect from moisture.
- Do not use the tablets after the expiry date (EXP) which is stated on the carton, wallet or blister. The expiry date refers to the last day of the month.
- Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
OTHER INFORMATION
What LUCEN contains
The active ingredient is esomeprazole. LUCEN gastro-resistant tablets are present in 2 strengths containing 20 or 40 mg of esomeprazole (as magnesium trihydrate).
The other ingredients are: glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide (red-brown, yellow) (E172, only for 20 mg tablets), magnesium stearate, methacrylic acid copolymer ethyl acrylate (1: 1) dispersion at 30%, microcrystalline cellulose, synthetic paraffin, macrogols, polysorbate 80, crospovidone, sodium stearyl fumarate, sucrose spheres (sucrose and corn starch), talc, titanium dioxide (E171), triethyl citrate.
Description of the appearance of LUCEN and contents of the pack
- LUCEN 20 mg gastro-resistant tablets are light pink with A / EH on one side and 20 mg on the other.
- LUCEN 40 mg gastro-resistant tablets are pink with A / EI on one side and 40 mg on the other.
- The tablets are in blister packs, wallets and / or bottles containing
- 20 mg, 40 mg: bottle of 2-5-7-14-15-28-30-56-60-100-140 (28x5) tablets.
- 20 mg, 40 mg: blister or wallet blister of 3-7-7x1-14-15-25x1-28-30-50x1- 56-60-90-98-100x1-140 tablets.
Not all pack sizes may be marketed
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)
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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)
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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. No differences due to treatment could be established in subclasses of this questionnaire. The difference between Lucentis 0.5 mg and the control group was assessed with a p-value of 0.0137 (ranibizumab mono) and 0.0041 (ranibizumab + laser ) for the composite score of the VFQ-25.
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
