Active ingredients: Prednisone
Lodotra 1 mg modified release tablets
Lodotra 2 mg modified release tablets
Lodotra 5 mg modified release tablets
Indications Why is Lodotra used? What is it for?
Lodotra is a delayed-release tablet that contains the active substance prednisone, a corticosteroid. Corticosteroids possess anti-inflammatory activity. Anti-inflammatory drugs reduce pain, swelling, stiffness, redness and heat in the affected joints.
Lodotra is used for the treatment of:
- moderate to severe active rheumatoid arthritis, particularly when accompanied by morning stiffness, in adults.
Lodotra tablets are modified release. This means that they are designed to release prednisone approximately 4 hours after taking. This allows you to take Lodotra at bedtime and feel an improvement in morning symptoms, such as stiffness.
Contraindications When Lodotra should not be used
DO NOT take Lodotra
- If you are allergic to prednisone or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Lodotra
Talk to your doctor or pharmacist before taking Lodotra You should tell your doctor if you have (at present) or have had (in the past) any of the following, or if you have had any of the following treatments:
- too high level of sugar (glucose) in the blood (diabetes). Your doctor may increase the dose of your diabetes medications and closely monitor your blood sugar levels
- weakening of the bones (osteoporosis)
- softening of the bones (osteomalacia)
- stomach and intestinal ulcers
- severe ulcerative colitis (inflammation of the colon) with a high risk of perforation (hole) in the colon
- inflammation of the intestine (diverticulitis)
- condition immediately following surgery to connect two parts of the intestine (entero-anastomosis)
- hepatitis B (liver disease caused by a virus)
- tuberculosis (TB), a "bacterial infection that usually affects the lungs
- swelling and inflammation of the lymph nodes after vaccination with BGC (a vaccination against tuberculosis)
- poliomyelitis (an infectious disease caused by a virus that affects the nervous system)
- vaccination within 8 weeks or 2 weeks after (if live vaccines are used)
- acute viral infection (eg chicken pox, cold sores or eye, measles or St. Anthony's fire)
- acute bacterial infection (e.g. bacterial tonsillitis) or chronic bacterial infections (e.g. tuberculosis)
- acute fungal infection (e.g. thrush)
- parasitic infection (e.g. ascariasis). In patients with suspected or known parasitic infection (Strongyloides), Lodotra may cause extensive infection and widespread migration of larvae.
- high blood pressure. You may need to have your blood pressure checked more frequently
- eye disease (glaucoma). Your condition may need to be monitored more closely
- recent heart attack
- kidney failure
- lesions or ulcers of the cornea (the clear front part of the eye that covers the iris and pupil)
- heart problems. Your condition may need to be monitored more closely
- mental disease
- sleep disturbances can occur during treatment without apparent improvement. In this situation, it may be advisable to switch to a conventional (immediate) release prednisone formulation.
Lodotra may not achieve desired blood concentrations of prednisone when taken on an empty stomach. Therefore, the drug must always be taken during or immediately after the evening meal in order to exert its effectiveness. In addition to this, it should be considered that, in 6-7% of patients who take Lodotra correctly, the levels in the blood are not sufficient. This fact must be considered if Lodotra is not as effective as it should be. In these situations, it may be advisable to switch to a conventional (immediate) release prednisone formulation.
Lodotra should not be taken for acute treatment in place of immediate-release prednisone tablets due to its pharmacological properties.
In one of the treatments or ailments mentioned above, another type of drug may be more suitable. See also "Other important information about Lodotra".
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
YOUR DOCTOR WILL ADVISE YOU WHAT TO DO.
Other important information about Lodotra
Lodotra can have an effect on the immune system.
This impairs its ability to fight infections. If your immune system is impaired:
- Vaccination with an inactivated vaccine (e.g. flu or cholera vaccine) may not be effective if you are taking or starting to take Lodotra.
- Some viral diseases (chicken pox and measles) can be more serious. If you have not been vaccinated against these diseases, you may be at particular risk.
- There may be a greater risk of other serious infections.
Treatment with Lodotra may increase the likelihood of developing an "infection. If you are developing an" infection, it may be more difficult to detect it while being treated with Lodotra. The dose of Lodotra may need to be reduced if you have:
- hypothyroidism (underactive thyroid gland)
- cirrhosis of the liver (liver disease caused by alcoholism or hepatitis).
The dose of Lodotra may need to be increased in case of stressful events, such as:
- A surgery
- an "infection in progress.
If you take Lodotra for several months or longer, your doctor will do periodic checks, such as:
- eye examination
- blood analysis
- blood pressure control.
Treatment with Lodotra can have a negative effect on the way calcium is metabolized in your bones. For this reason, you should clarify the risk of osteoporosis (bone loss and fractures) with your doctor, particularly if you have family members with a history of bone fractures, if you do not exercise regularly, if you are a woman in or postmenopause or if you are elderly.
When treatment with Lodotra is stopped, there is a risk of:
- reappearance of rheumatoid arthritis symptoms
- adrenal insufficiency. This occurs when the adrenal gland does not produce enough cortisol (a hormone), which is particularly likely in stressful situations, for example: - with ongoing infections - after an accident - if you are subjected to increased physical fatigue
- cortisone withdrawal syndrome (a serious illness caused by the body not producing cortisol).
YOUR DOCTOR WILL ADVISE YOU WHAT TO DO.
Interactions Which drugs or foods can modify the effect of Lodotra
Other medicines and Lodotra
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Treatment with Lodotra may potentiate the effects of the following medicines:
- heart medications, such as cardiac glycosides (e.g. digoxin)
- laxatives or drugs that reduce the level of salts, eg. some diuretics (drugs that increase urine production)
- ciclosporin, a drug used after transplantation or occasionally in severe rheumatoid arthritis
- muscle relaxants, such as suxamethonium, used in hospitals
- cyclophosphamide, a treatment for various types of cancer.
Treatment with Lodotra may reduce the effects of the following medicines:
- somatropin, a growth hormone
- praziquantel, a treatment for parasitic infections
- medicines for diabetes, eg. insulin, metformin, glibenclamide.
The following medicines may reduce the effect of Lodotra on the symptoms of rheumatoid arthritis:
- treatments for epilepsy, such as barbiturates, phenytoin and primidone
- rifampicin, a treatment for infections
- bupropion, a treatment for depression
- antacids based on aluminum and magnesium.
The following medicines may increase the effect of Lodotra on the symptoms of rheumatoid arthritis:
- medicines containing estrogen, eg. oral contraceptives, hormone replacement therapy (HRT) • licorice (used as an expectorant in cough medicines and also found in confectionery).
Other effects of medicines:
- non-steroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, diclofenac, and ibuprofen, increase the risk of gastrointestinal bleeding
- warfarin could cause a decrease or increase in blood-thinning effects, depending on the person
- treatment with ACE inhibitors (eg captopril or enalapril) for high blood pressure or heart failure may increase the risk of changes in blood counts
- anticholinergic medicines (eg atropine) may carry an increased risk of increased pressure in the eye (glaucoma)
- Medicines for the treatment or prevention of malaria (e.g. chloroquine, hydroxychloroquine, mefloquine) may increase the risk of muscle weakness, including heart muscle weakness
- amphotericin B, an antifungal drug, may increase the risk of hypokalaemia
- some diagnostic tests may be altered, for example: - skin tests for allergies - blood tests to measure the levels of a hormone produced by the thyroid gland.
YOUR DOCTOR WILL ADVISE YOU WHAT TO DO.
Lodotra with food and drink
Take Lodotra in the evening, usually around 10pm. Ideally you should take your Lodotra modified release tablets with or after your evening meal. Lodotra modified-release tablets should be swallowed whole, with a sufficient amount of fluid, e.g. a glass of water.
You must NOT break, divide or chew the tablets.
Also, if more than 2-3 hours have passed since food, take the tablets with a light meal or snack.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Driving and using machines
Lodotra is unlikely to affect the ability to drive or use machines. However, if you experience pain in your eyes or blurring of vision during treatment you should avoid these activities.
Lodotra contains lactose
The medicine contains a sugar called lactose. If you have been diagnosed with "intolerance to some sugars, consult your doctor before taking Lodotra.
Dose, Method and Time of Administration How to use Lodotra: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The dose of Lodotra that your doctor prescribes depends on the severity of the disease. Usually it shouldn't exceed 10 mg of prednisone per day.
The starting dose on the advice of the doctor can be gradually reduced to a lower maintenance dose based on:
- the symptoms of rheumatoid arthritis
- to the answer to Lodotra.
For dosages not feasible with this strength, other strengths of this medicinal product are also available.
If you switch from taking standard glucocorticoid tablets in the morning to taking Lodotra in the evening, the dose should contain the same amount of active ingredient (prednisone).
Method of administration:
- How to open and close the bottle of Lodotra designed specifically for patients with rheumatoid arthritis: see "Instructions for" opening and closing the container "
- Take the number of tablets prescribed by your doctor
- Do not break the tablet, as the integrity of the coating is important for the effectiveness of Lodotra
- Swallow the tablets whole: do not break, split or chew the tablets
- Take Lodotra in the evening (usually around 10 pm) with a glass of water
- You must take Lodotra with or after your evening meal. If it is more than 2-3 hours after food, take the tablet with a light meal or snack
- Always take the tablets after dinner or a light snack.
Lodotra modified-release tablets are usually taken for several months or longer. Your doctor will discuss with you how long the treatment will take.
Instructions for opening and closing the container:
Follow the instructions below:
To open: Insert a pen or similar object between the raised sections of the lid and rotate in the direction shown (counterclockwise).
To close: Insert a pen or similar object between the raised sections of the lid and rotate in the direction shown (clockwise).
Overdose What to do if you have taken too much Lodotra
If you take more Lodotra than you should
There are no known cases of acute intoxication with Lodotra. In the event of an overdose, an increase in undesirable effects is likely, such as:
- disturbances of hormonal function
- effects on metabolism
- effects on electrolyte balance (salts), which leads to an increased risk of abnormal heart beat.
CONTACT YOUR DOCTOR IF YOU ARE WORRIED OR IF YOU NOTICE AN INCREASE IN ADVERSE EFFECTS
If you forget to take Lodotra
CONTACT YOUR DOCTOR TO KNOW HOW TO BEHAVE
If you stop using Lodotra
Do not suddenly stop taking Lodotra modified release tablets.
If you stop using Lodotra your rheumatoid arthritis symptoms may come back.
It is important to reduce the Lodotra dose slowly. Your doctor will advise you on how to gradually reduce the dose.
Lodotra should not be replaced with immediate-release prednisone tablets without first consulting your doctor.
IF YOU HAVE ANY DOUBTS ABOUT THE USE OF THIS MEDICINAL PRODUCT, PLEASE ASK YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Lodotra
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The frequency and severity of the side effects listed below depends on the dosage and duration of treatment.
Common side effects of Lodotra (may affect up to 1 in 10 people):
Hormonal imbalance causing Cushing's syndrome (typical symptoms: round face, often called "full moon face", weight gain in the upper body and rash on the face) as well as a decrease in the production of glucocorticoids in the body.
Disturbances in the balance of sugars, fats and salts in the body, which can cause:
- increased appetite and body weight
- diabetes
- high cholesterol
- heart rhythm disturbances (due to "increased" potassium excretion)
- accumulation of water (edema, due to reduced sodium excretion).
Reduced ability to fight infections. Infections may be more severe or symptoms may be masked. Increased susceptibility and severity of infections. Lens opacity (cataract) and increased eye pressure (glaucoma) with or without eye pain. Stretch marks, bruises or red spots on the skin or inside the mouth, deterioration of the skin. Increase or decrease in the number of blood cells. Muscle deterioration and weakness, bone deterioration leading to an increased risk of bone fractures (osteoporosis ) Headache Difficulty sleeping.
Uncommon side effects of Lodotra (may affect up to 1 in 100 people):
- High pressure.
- Thickening or inflammation of the lining of blood vessels and blood clots.
- Stomach ulcers and intestinal bleeding.
- Increased growth of hair, spots or other skin imperfections and delayed healing of skin wounds, acne.
Rare side effects of Lodotra (may affect up to 1 in 1000 people):
- Allergic reactions, including blistering of the skin.
- Inflammation of the pancreas, which causes severe abdominal pain.
- Disorders of the secretion of sex hormones, which can cause: absence of the menstrual cycle in women or impotence in men.
- Thyroid function disorder.
- Depression (feeling of sadness), irritability, feelings of happiness not justified by reality, increased impulsiveness, loss of contact with reality (psychosis).
- Increased pressure in the head, which causes headaches, vomiting and double vision.
- Development or aggravation of seizures.
- Worsening of existing eye ulcers or infections.
- Bone loss (osteonecrosis)
Side effects of Lodotra, with frequency not known (frequency cannot be estimated from the available data):
- Reversible accumulation of fat in the back, heart and chest (lipomatosis).
- Accelerated heartbeat.
- Acid-base blood imbalance due to low potassium levels (hypokalaemic alkalosis).
- Distortion of vision due to fluid loss from the retina (central serous chorioretinopathy).
- Nausea, diarrhea, vomiting.
- Hair growth in women (hirsutism)
- Muscle atrophy of the upper arms and legs, rupture of tendons, vertebral and long bone fractures
Adverse Event Reporting:
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.You can also report the adverse event directly through the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting the adverse event you will help provide more information on the safety of this medicine.
IF ANY UNDESIRABLE EFFECTS OCCUR, INCLUDING THOSE NOT LISTED IN THIS LEAFLET, CONTACT YOUR DOCTOR OR PHARMACIST
Expiry and Retention
How to store Lodotra
- 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 bottle and carton. The expiry date refers to the last day of the month.
- After opening the container, the tablets can be stored in the bottle for up to 14 weeks. After this time, throw away the remaining tablets.
- Do not store above 25 ° C
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Lodotra contains
The active ingredient is prednisone.
One Lodotra 1 mg modified-release tablet contains 1 mg of prednisone.
One Lodotra 2 mg modified-release tablet contains 2 mg of prednisone.
One Lodotra 5 mg modified-release tablet contains 5 mg of prednisone
The other ingredients are:
Tablet core:
- Anhydrous colloidal silica
- Croscarmellose sodium
- Lactose monohydrate
- Magnesium stearate
- Povidone K 29/32
- Red iron oxide E172.
Tablet coating:
- Anhydrous colloidal silica
- Calcium hydrogen phosphate dihydrate
- Glycerol dibeenate
- Magnesium stearate
- Povidone K 29/32
- Yellow iron oxide E172.
Description of the appearance of Lodotra and contents of the pack
Lodotra 1 mg modified release tablets are pale yellowish white, cylindrical tablets embossed with "NP1" on one side.
Lodotra 2 mg modified-release tablets are yellowish-white, cylindrical tablets embossed with "NP2" on one side.
Lodotra 5 mg modified release tablets are light yellow, cylindrical tablets embossed with "NP5" on one side.
Pack sizes: Bottles of 30 and 100 modified release tablets.
Hospital packs: bottles of 30, 100 and 500 modified release 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
LODOTRA MODIFIED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lodotra 1 mg:
one modified-release tablet contains 1 mg of prednisone.
Lodotra 2 mg:
one modified-release tablet contains 2 mg of prednisone.
Lodotra 5 mg:
one modified-release tablet contains 5 mg of prednisone.
Excipient with known effect: lactose.
Lodotra 1 mg:
each modified-release tablet contains 42.80 mg of lactose.
Lodotra 2 mg:
each modified-release tablet contains 41.80 mg of lactose.
Lodotra 5 mg:
each modified-release tablet contains 38.80 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Modified-release tablets.
Lodotra 1 mg:
pale yellowish white, cylindrical modified release tablets, 5 mm thick and 9 mm in diameter, embossed with "NP1" on one side.
Lodotra 2 mg:
White to yellowish, cylindrical modified release tablets, 5 mm thick and 9 mm in diameter, embossed with "NP2" on one side.
Lodotra 5 mg:
light yellow colored, cylindrical modified release tablets, 5 mm thick and 9 mm in diameter, with "NP5" embossed on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Lodotra is indicated for the treatment of moderate or severe active rheumatoid arthritis, particularly when accompanied by morning stiffness, in adults.
04.2 Posology and method of administration
Dosage
The correct dose depends on the severity of the disorder and the patient's individual response. Generally, 10 mg of prednisone is recommended for initiation of therapy. In some cases, a higher starting dose (eg 15 or 20 mg prednisone) may be required. Depending on clinical symptoms and patient response , the starting dose may be gradually reduced to a lower maintenance dose.
When switching from the standard regimen (administration of glucocorticoids in the morning) to Lodotra administered at bedtime (approximately 10 pm), the same posology (in mg prednisone equivalent) should be maintained. Once the switch is made, the dose can be adjusted according to the clinical situation.
For dosages not feasible with this strength, other strengths of this medicinal product are available. For the long-term therapy of rheumatoid arthritis the individual dose of up to 10 mg of prednisone per day should be adjusted according to the severity of the disease course.
Depending on the outcome of the treatment, the dose may be reduced at intervals of 1 mg every 2-4 weeks in order to achieve the appropriate maintenance dose.
To discontinue therapy with Lodotra, the dose should be reduced at 1 mg intervals every 2-4 weeks, monitoring the pituitary-adrenal axis parameters if necessary.
Pediatric population
Use in children and adolescents is not recommended due to insufficient data on tolerability and efficacy.
Method of administration
Lodotra should be taken at bedtime (around 10pm), during or after the evening meal and the tablets should be swallowed whole with a sufficient amount of liquid. If more than 2-3 hours have passed since the evening meal, it is recommended to take Lodotra together with a light meal or snack (e.g. a slice of bread with ham or cheese). Lodotra should not be administered in the fasting state, as this may reduce its bioavailability.
Lodotra is designed to release the active ingredient with a delay of approximately 4-6 hours from intake. The release of the active ingredient and pharmacological effects will then begin during the night.
Modified-release Lodotra tablets consist of a core containing prednisone and an inert coating. The delayed release of prednisone depends on the integrity of the coating. For this reason, modified-release tablets should not be broken, divided or chewed. In patients with hypothyroidism or liver cirrhosis, relatively low dosages may be sufficient, or a reduction may be necessary. of the dose.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Prednisone-based drug therapy should only be prescribed in case of absolute necessity and must be accompanied by "appropriate anti-infective therapy in the presence of the following conditions:
- Acute viral infections (herpes zoster, herpes simplex, chicken pox, herpetic keratitis)
- HBsAg-positive chronic active hepatitis
- Approximately 8 weeks before and 2 weeks after immunization with live vaccines
- Systemic mycoses and parasites (e.g. roundworms)
- Poliomyelitis
- Lymphadenitis following BCG inoculation
- Acute and chronic bacterial infections
- History of tuberculosis (attention: reactivation!). Due to their immunosuppressive properties, glucocorticoids can induce or aggravate infections. Such patients should be kept under close observation, eg. doing a tuberculin test. Patients at particular risk should undergo tuberculostatic treatment.
In addition, prednisone-based drug therapy should only be prescribed in case of absolute necessity and should be accompanied, if necessary, by "appropriate therapy in the presence of the following conditions:
- Gastrointestinal ulcers
- Severe osteoporosis and osteomalacia
- Hypertension difficult to control
- Severe diabetes mellitus
- Psychiatric disorders (even if in the patient's previous medical history)
- Closed-angle and open-angle glaucoma
- Corneal ulcers and corneal lesions.
Due to the risk of intestinal perforation, prednisone can only be used when absolutely necessary and with adequate monitoring in the presence of:
- Severe ulcerative colitis with impending perforation
- Diverticulitis
- Entero-anastomosis (immediately post-operative).
The optimal blood concentration of prednisone cannot be achieved if Lodotra is taken in the fasted state. Therefore, the drug should always be taken during or after the evening meal in order to ensure sufficient efficacy. In addition, even if the drug is taken correctly, low plasma concentrations may occur in 6-7% of Lodotra administrations, as a result of all pharmacokinetic studies, and in 11% of administrations in a single pharmacokinetic study. in consideration if Lodotra is not sufficiently effective. In these situations, the desirability of a conventional immediate release formulation should be considered.
Lodotra should not be replaced by immediate-release prednisone tablets within the same administration regimen due to Lodotra's delayed release mechanism.
In case of replacement, termination or interruption of a prolonged treatment, the following risks must be considered: recurrence of rheumatoid arthritis, acute adrenal insufficiency (especially in stressful situations, for example during infectious processes, after accidents, or during intense physical activity ), cortisone withdrawal syndrome.
Lodotra should not be administered for acute indications in place of immediate-release prednisone tablets due to its pharmacological properties.
While taking Lodotra, a possible increase in insulin or oral antidiabetic needs should be considered. Patients with diabetes mellitus should therefore be treated under careful supervision.
Regular blood pressure checks are required during treatment with Lodotra in patients with hypertension that is difficult to control.
Patients with severe heart failure should be closely monitored due to the risk of disease aggravation.
Special precautions should be taken whenever corticosteroids, including prednisone, are prescribed to patients with recent myocardial infarction due to the risk of myocardial rupture.
Special precautions should be taken whenever corticosteroids, including prednisone, are prescribed to patients with renal insufficiency.
Sleep disturbances can occur more frequently after taking Lodotra than with conventional immediate-release formulations that are taken in the morning. If insomnia develops and does not improve, it may be advisable to switch to conventional immediate-release prednisone tablets.
Treatment with Lodotra can also mask the signs and symptoms of an existing or developing infection, thus making diagnosis more difficult.
Even at low doses, prolonged use of Lodotra carries an increased risk of infections. Such possible infections can also be caused by microorganisms that rarely cause infection under normal circumstances (so-called opportunistic infections).
Some viral diseases (chicken pox, measles) may have a more severe course in patients treated with glucocorticoids. Immunosuppressed individuals with no previous chickenpox or measles infection are at particular risk. If, during treatment with Lodotra, such individuals have contact with people infected with chickenpox or measles, preventive treatment should be instituted if necessary.
In patients with suspected or known Strongyloides (parasites) infestation, glucocorticoids can cause superinfection and dissemination with "extensive migration of larvae."
Vaccinations with inactivated vaccines are generally possible. However, it must be considered that the immune response and, consequently, the success of vaccination may be compromised by the administration of high doses of glucocorticoids.
In case of prolonged therapy with Lodotra, regular follow-up medical checks are indicated (including ophthalmological examinations every three months); if relatively high doses are administered, a sufficient intake of potassium supplements and a restriction of sodium intake should be ensured, and serum potassium levels should be monitored.
If certain events (accidents, surgical procedures, etc.) cause high levels of physical stress during treatment with Lodotra, a temporary dose increase may be necessary.
Depending on the duration of treatment and the dosage employed, a negative impact on calcium metabolism is to be expected. Therefore, osteoporosis prophylaxis is recommended, particularly important if other risk factors are present (such as family predisposition, old age, postmenopausal state, insufficient protein and calcium intake, excessive smoking, excessive alcohol consumption and reduced physical activity). Prophylaxis is based on a sufficient intake of calcium and vitamin D, as well as physical activity. In case of pre-existing osteoporosis, additional therapy should be considered.
The medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
With the use of high doses of prednisone for a prolonged period (30 mg / day for a minimum of 4 weeks), reversible disorders of spermatogenesis have been observed, lasting for several months after discontinuation of the drug.
04.5 Interactions with other medicinal products and other forms of interaction
Cardiac glycosides: the effect of glycosides can be enhanced by potassium deficiency.
Saluretics / Laxatives: Potassium excretion is increased.
Antidiabetic agents: the hypoglycemic effect is reduced.
Coumarin derivatives: the efficacy of coumarin anticoagulants can be reduced or enhanced.
Non-steroidal anti-inflammatory / antirheumatic agents, salicylates and indomethacin: the risk of gastrointestinal bleeding is increased.
Non-depolarizing muscle relaxants: muscle relaxation can be prolonged.
Atropine and other anticholinergics: concomitant use of Lodotra may lead to a further increase in intraocular pressure.
Praziquantel: Glucocorticoids may reduce the blood concentrations of praziquantel.
Chloroquine, hydroxychloroquine, mefloquine: there is a greater risk of the appearance of myopathies and cardiomyopathies.
Somatropin: The efficacy of somatropin may be reduced.
Estrogen (eg oral contraceptives): can increase the efficacy of glucocorticoids.
Licorice: inhibition of glucocorticoid metabolism is possible.
Rifampicin, phenytoin, barbiturates, bupropion and primidone: the efficacy of glucocorticoids is reduced.
Ciclosporin: blood levels of cyclosporine increase. There is an increased risk of seizures.
Amphotericin B: May increase the risk of hypokalaemia.
Cyclophosphamide: the effects of cyclophosphamide can be enhanced.
ACE inhibitors: increased risk of changes in the blood count.
Antacids based on aluminum and magnesium: reduce the absorption of glucocorticoids. However, given the delayed release of Lodotra, such an interaction is unlikely.
Impact on diagnostic methods: skin reactions caused by allergen tests can be suppressed.
The increase in TSH after administration of protirelin can be reduced.
04.6 Pregnancy and lactation
Pregnancy
In pregnancy, Lodotra should only be used if the benefits outweigh the potential risks.The lowest effective dose of Lodotra needed to maintain adequate disease control should be used.
Animal studies indicate that the administration of pharmacological doses of glucocorticoids during pregnancy may increase the fetal risk of intrauterine growth retardation, cardiovascular and / or metabolic disease in adulthood and may have an effect on glucocorticoid receptor density and on neurotransmitter turnover or neurobehavioral development.
Prednisone caused cleft palate formation in animal experiments (see section 5.3). The possible increased risk of orofacial cleft formation in the human fetus, following the administration of glucocorticoids during the first trimester of pregnancy, is currently under debate.
If glucocorticoids are administered towards the end of pregnancy, there is a risk of atrophy of the fetal adrenal cortex, which may require replacement therapy in the neonate, to be progressively reduced.
Feeding time
Glucocorticoids pass in small quantities into breast milk (up to 0.23% of the single dose). For doses up to 10 mg / day, the amount taken through breast milk is below the detection threshold. No harm to infants has been reported so far. However, glucocorticoids should only be prescribed when the benefits to the mother and child outweigh the risks.
Since the milk / plasma concentration ratio increases with doses above 10 mg / day (e.g. 25% of the serum concentration is found in breast milk with 80 mg prednisone / day), it is recommended to discontinue breastfeeding in such cases. .
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
The frequency and severity of the side effects listed below depend on the dosage and duration of treatment. In the recommended dose range for Lodotra (low dose corticoid therapy, 1 to 10 mg daily), the listed side effects occur less frequently and less severely than with doses above 10 mg.
The following side effects may occur, depending on the duration of treatment and dosage:
very common (≥1 / 10); common (≥1 / 100,
Disorders of the blood and lymphatic system:
Common: moderate leukocytosis, lymphopenia, eosinopenia, polycythemia
Cardiac disorders:
Not known: tachycardia
Immune system disorders:
Common: decreased immune defenses, masking of infections, exacerbation of latent infections
Rare: allergic reactions
Infections and infestations:
Common: increased susceptibility and severity to infections
Endocrine disorders:
Common: adrenal suppression and induction of Cushing's syndrome (typical symptoms: lunar facies, upper body obesity and plethora)
Rare: impaired secretion of sex hormones (amenorrhea, impotence), disturbance of thyroid function
Metabolism and nutrition disorders:
Common: sodium retention with edema, increased potassium excretion (attention: arrhythmias), increased appetite and weight gain, impaired glucose tolerance, diabetes mellitus, hypercholesterolemia and hypertriglyceridaemia
Not known: epidural, epicardiac or mediastinal reversible lipomatosis, hypokalaemic alkalosis
Psychiatric disorders:
Common: insomnia
Rare: depression, irritability, euphoria, increased impulsivity, psychosis
Nervous system disorders:
Common: headache
Rare: pseudotumor cerebri, manifestation of latent epilepsy and increased predisposition to develop seizures in case of manifest epilepsy
Eye disorders:
Common: cataract, particularly with posterior subcapsular opacity, glaucoma
Rare: aggravation of symptoms associated with corneal ulcer, promotion of viral, fungal and bacterial ocular inflammations
Not known: central serous chorioretinopathy
Vascular disorders:
Uncommon: hypertension, increased risk of atherosclerosis and thrombosis, vasculitis (also as withdrawal syndrome after prolonged therapy)
Gastrointestinal disorders:
Uncommon (without concomitant NSAIDs): gastrointestinal ulceration, gastrointestinal haemorrhage
Rare: pancreatitis
Not known: nausea, diarrhea, vomiting
Skin and subcutaneous tissue disorders:
Common: striae rubre, atrophy, telangiectasia, increased capillary fragility, petechiae, ecchymosis
Uncommon: hypertrichosis, steroid acne, delayed wound healing, rosaceous (perioral) dermatitis, skin pigmentation changes
Rare: hypersensitivity reactions, eg. drug rash
Not known: hirsutism
Musculoskeletal and connective tissue disorders:
Common: muscle atrophy and weakness, osteoporosis (dose-related, may also occur with short-term use)
Rare: aseptic osteonecrosis (humeral and femoral head)
Not known: steroid myopathy, tendon rupture, vertebral and long bone fractures
Adverse Event Reporting:
The reporting of suspected adverse reactions occurring after 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 national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
There are no known cases of acute intoxication with Lodotra. In the event of overdose, an increase in undesirable effects, especially endocrine, metabolic and electrolyte effects, can be expected (see section 4.8).
There is no known antidote for prednisone.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: glucocorticoids.
ATC code: H02AB07.
Prednisone is a non-fluorinated glucocorticoid for systemic therapy.
Prednisone exhibits a dose-dependent effect on the metabolism of almost all tissues. Under physiological conditions, these effects are vital for maintaining the body's homeostasis at rest and under stress, as well as for controlling the activities of the immune system.
At the doses typically prescribed for Lodotra, prednisone has an immediate anti-inflammatory (antiexudative and antiproliferative) effect and a delayed immunosuppressive effect. It inhibits chemotaxis and the activity of immune cells, as well as the release and effect of mediators of inflammatory and immune reactions, eg. lysosomal enzymes, prostaglandins and leukotrienes.
Prolonged therapy at high doses involves an "alteration of the response of the immune system and the adrenal cortex. The mineraltropic effect, pronounced in hydrocortisone, is however detectable in prednisone and may require monitoring of serum electrolyte levels."
In patients with rheumatoid arthritis, proinflammatory cytokines, such as interleukins IL-1 and IL-6 and tumor necrosis factor alpha (TNFα), peak in plasma early in the morning (e.g. IL-6 between 7am and 8 o'clock). There was a reduction in cytokine concentrations after administration of Lodotra and subsequent nocturnal release of prednisone (with onset of absorption between 2 and 4 in the morning and Cmax between 4 and 6).
The efficacy and safety of Lodotra was demonstrated in two randomized, double-blind, controlled studies in patients with active rheumatoid arthritis.
In the first multicenter, randomized, double-blind, 12-week phase III study involving a total of 288 patients pre-treated with prednisone or prednisolone, the group switched to Lodotra at the same dose showed an average reduction of 23 % duration of morning stiffness, while duration in the reference group remained unchanged. Details are shown in the following table.
Relative change in duration of morning stiffness after 12 weeks of treatment:
In a subsequent open-label extension phase (9 months of treatment), the mean relative change in duration of morning stiffness from baseline was approximately -50%.
Change in duration of morning stiffness after 12 months of treatment with Lodotra
In the same study, after 12 weeks of treatment, a median reduction of 29% in proinflammatory cytokine IL-6 was observed in the Lodotra-treated group, while no change was observed in the comparator group administered standard prednisone. . After 12 months of treatment with Lodotra the level of IL-6 remains stable.
Change in IL-6 level after 12 months
For statistical analyzes, the values
The efficacy of Lodotra given as an adjunct to DMARDs was confirmed in a second randomized, placebo-controlled study in patients who responded poorly to DMARD therapy alone.
At 12 weeks, patients treated with Lodotra had a significant increase in the rate of ACR 20 and ACR50 responses (46.8% and 22.1%, respectively) compared to patients treated with placebo (29.4% and 10.1%, respectively. ). There was also a greater change in the mean DAS28 score from baseline (5.2 for the Lodotra group and 5.1 for the placebo group) at week 12 in the Lodotra group (- 1.2 points) when compared with what was observed in the placebo group (- 0.7 points).
In addition, after 12 weeks of therapy, the mean duration of morning stiffness was 86.0 minutes (- 66 minutes of change) in the Lodotra group and 114.1 minutes (- 42.6 minutes of change) in the placebo group. Lodotra could be safely used in conjunction with other DMARDs.
05.2 "Pharmacokinetic properties
Absorption
Lodotra tablets are modified release tablets containing prednisone. Prednisone is released 4-6 hours after taking Lodotra. Thereafter, prednisone is absorbed rapidly and almost completely.
Distribution
Serum peaks are reached approximately 6-9 hours after intake.
Biotransformation
More than 80% of prednisone is converted to prednisolone by hepatic first pass metabolism. The prednisone-prednisolone ratio is approximately 1: 6 to 1:10. Prednisone itself has negligible pharmacological effects. Prednisolone is the active metabolite. The compounds bind reversibly to plasma proteins, with high affinity for transcortin (corticosteroid-binding globulin, CBG) and low affinity for plasma albumin.
In the low dose range (up to 5 mg), approximately 6% of free prednisolone is present. Metabolic elimination is dose-linear in this range. In the "dose range above 10 mg, transcortin binding capacity is progressively depleted and more free prednisolone is present. This may result in faster metabolic elimination."
Elimination
Prednisolone is eliminated primarily by hepatic metabolism, from about 70% by glucuronidation and to about 30% by sulfation. There is also a conversion to 11β, 17β-dihydroxandrost-1,4-dien & ndas h; 3-one and to 1,4-pregnadien-20-ol. The metabolites do not exhibit hormonal activity and undergo mainly renal elimination. Negligible amounts of prednisone and prednisolone are found unchanged in the urine. The plasma elimination half-life of prednis (ol) one is approximately 3 hours. In patients with severe hepatic dysfunction, the half-life may be prolonged and a dose reduction should be considered. The duration of biological effects of prednis (ol) one is greater than the duration of its presence in serum.
Bioavailability
A bioavailability study in 27 healthy subjects, conducted in 2003, revealed the following results compared to an immediate-release prednisone tablet:
The plasma concentration profiles of Lodotra are very similar to those of an immediate release tablet, with the important difference that the Lodotra profile is delayed by 4-6 hours after taking the drug. Lower plasma concentrations were observed in 6-7% of doses.
Dose proportionality was demonstrated for Lodotra 1 mg, 2 mg and 5 mg based on AUC and Cmax.
05.3 Preclinical safety data
Subchronic / chronic toxicity
Light and electron microscopic changes were observed in Langerhans islet cells in rats after daily intraperitoneal administration of 33 mg / kg body weight over 7-14 days in rats. In rabbits, experimental liver damage could be produced. administered 2-3 mg / kg body weight / day, for 2-4 weeks. Histotoxic effects (myonecrosis) have been reported after several weeks of administration of 0.5-5 mg / kg body weight in guinea pigs and 4 mg / kg of body weight in dogs.
Mutagenic and oncogenic potential
Toxicity observed in animal studies with prednisone was associated with "excessive pharmacological activity. No genotoxic effects of prednisone were observed in conventional genotoxicity tests."
Reproductive toxicity
In animal reproduction studies, glucocorticoids such as prednisone have been shown to induce malformations (cleft palate, skeletal malformations). Minor anomalies of the skull, jaw and tongue were found in rats with parenteral administration. Intrauterine growth retardation has been observed (see also section 4.6).
Similar effects are considered unlikely in patients at therapeutic doses.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Anhydrous colloidal silica
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Povidone K 29/32
Red iron oxide E172
Tablet coating:
Anhydrous colloidal silica
Calcium hydrogen phosphate dihydrate
Glycerol dibeenate
Magnesium stearate
Povidone K 29/32
Yellow iron oxide E172
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
Shelf life after opening the bottle: 14 weeks.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Container with 30 and 100 modified release tablets:
White high-density polyethylene (HDPE) bottle. Screw cap (containing a desiccant capsule) in HDPE with three raised points arranged around the edge, to facilitate opening.
Container with 500 modified-release tablets:
White high density polyethylene bottle (with a small amount of LDPE). Polypropylene screw cap (without three raised points).
Pack sizes: Bottles of 30 and 100 modified release tablets
Hospital packs: bottles of 30, 100 and 500 modified release tablets
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Mundipharma Pharmaceuticlas Srl
Via G. Serbelloni 4
20122 Milan
Italy
08.0 MARKETING AUTHORIZATION NUMBER
Lodotra 1 mg:
AIC n. 038986016 1 mg modified release tablets, 30 tablets in HDPE bottle
AIC n. 038986028 1 mg modified release tablets, 100 tablets in HDPE bottle
AIC n. 038986030 1 mg modified-release tablets, 30 tablets in HDPE bottle (hospital pack)
AIC n. 038986042 1 mg modified release tablets, 100 tablets in HDPE bottle (hospital pack)
AIC n. 038986055 1 mg modified release tablets, 500 tablets in HDPE bottle (hospital pack)
Lodotra 2 mg:
AIC n. 038986067 2 mg modified release tablets, 30 tablets in HDPE bottle
AIC n. 038986079 2 mg modified release tablets, 100 tablets in HDPE bottle
AIC n. 038986081 2 mg modified-release tablets, 30 tablets in HDPE bottle (hospital pack)
AIC n. 038986093 2 mg modified release tablets, 100 tablets in HDPE bottle (hospital pack)
AIC n. 038986105 2 mg modified-release tablets, 500 tablets in HDPE bottle (hospital pack)
Lodotra 5 mg:
AIC n. 038986117 5 mg modified release tablets, 30 tablets in HDPE bottle
AIC n. 038986129 5 mg modified release tablets, 100 tablets in HDPE bottle
AIC n. 038986131 5 mg modified-release tablets, 30 tablets in HDPE bottle (hospital pack)
AIC n. 038986143 5 mg modified release tablets, 100 tablets in HDPE bottle (hospital pack)
AIC n. 038986156 5 mg modified release tablets, 500 tablets in HDPE bottle (hospital pack)
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
November 2010
10.0 DATE OF REVISION OF THE TEXT
05/2015
