Active ingredients: Lithium (Lithium carbonate)
Carbolithium 150 mg hard capsules
Carbolithium 300 mg hard capsules
Why is Carbolithium used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antipsychotics
THERAPEUTIC INDICATIONS
Prophylaxis and treatment of states of excitement in manic and hypomanic forms and states of depression or chronic depressive psychosis of manic-depressive psychosis.
Cluster headache only in subjects who do not respond to other therapy, due to the low therapeutic index of lithium carbonate.
Contraindications When Carbolithium should not be used
Hypersensitivity to the active substance or to any of the excipients.
Lithium salts are contraindicated in:
- heart disease,
- kidney failure,
- severe state of debilitation,
- increased sodium depletion,
- concomitant treatment with diuretics,
- Known or suspected pregnancy and lactation (see Special Warnings).
The safety and efficacy of lithium salts in children under the age of 12 has not yet been established, therefore their use in such patients is not recommended, unless otherwise advised by the specialist.
Precautions for use What you need to know before taking Carbolithium
Lithium salts have a low therapeutic index (narrow therapeutic / toxic ratio) and therefore should not be prescribed if their blood concentration cannot be controlled.
It is always necessary to start therapy with low doses of the drug and titrate the dose according to the measurement of lithemia.
At the beginning of the therapy it is advisable to carry out the first determination of the lithemia upon reaching the steady state, ie after 4-8 days of the beginning of the therapy itself, on a blood sample taken 10-12 hours after the last administration.
Then repeat the lithemia measurement every week until the dosage remains constant for another four weeks, and then every three months.
Dose adjustments should be made to keep lithemia in the 0.4-1 mEq / liter range.
Plasma concentrations between 0.8 and 1 mEq / liter are usually required for the treatment of acute mania.
Recurrence prevention is generally achieved with plasma concentrations ranging from 0.6 to 0.75 mEq / liter, but some patients are also controlled by lower concentrations of 0.4-0.6 mEq / liter.
It is necessary to monitor the lithemia and the clinical status of the patient after each dose increase and to carry out constant checks during the entire duration of therapy and in particular in the case of intercurrent diseases (including urinary tract infections), alternation of manic and depressive phases, introduction of new drugs, and changes in diet with changes in the intake of salts and liquids.
Bioavailability varies greatly in different preparations: replacing one preparation with another requires the same precautions as for initiation of treatment, careful monitoring of lithemia, consequent dose adjustments and the physician's assessment of the patient's clinical status
Prior to initiating therapy with lithium salts it is advisable to evaluate cardiac, renal and thyroid function. These tests must be repeated periodically during therapy.
Pre-existing mild thyroid disorders are not necessarily a contraindication to lithium treatment; where hypothyroidism exists, thyroid function must be controlled both during the attack phase and during maintenance. In case of manifestation of hypothyroidism during therapy, it is advisable to carry out a "suitable replacement therapy with thyroid hormones. Renal and thyroid function should be checked every 6-12 months in stable regimens (unless otherwise prescribed).
During lithium therapy, patients should undergo regular blood count monitoring.
Lithium therapy should be used with caution in patients with cardiovascular disease or a family history of QT interval prolongation.
Lithium therapy must not be initiated in patients with renal insufficiency (see side effects). Patients with severe renal impairment treated with lithium for more than 10 years may be at risk of developing benign or malignant kidney cancer (microcyst, oncocytoma or renal cell carcinoma of the collecting ducts)
During lithium salt therapy, gradual or sudden changes in renal function, even if within normal limits, indicate the need for review of treatment.
Lithium salt therapy is not recommended in patients with Addison's disease or other conditions associated with sodium depletion and in severely debilitated or dehydrated patients. Lithium toxicity is increased by sodium depletion.
A decrease in lithium tolerability can be caused by body dehydration (profuse sweating, diarrhea, vomiting); in these cases, patients should be advised to increase the administration of salts and liquids and to notify the physician.
In the event that the aforementioned disorders are accompanied by an "infection with high temperature, a temporary dose reduction or interruption of treatment is recommended, always under strict medical supervision. Reduced renal excretion of lithium has been observed in patients with cystic fibrosis. Particular cautions in cystic fibrosis. "Determination of the lithium dose should be adopted in patients with myasthenia gravis to avoid exacerbation of the disease.
Given the potential teratogenicity of lithium, it is recommended in fertile women to carry out a pregnancy test before starting therapy (see Contraindications and Special warnings).
Although there is no clear evidence of withdrawal symptoms or rebound psychosis, abrupt discontinuation of lithium increases the risk of relapse. If treatment is to be discontinued, the dose should be gradually reduced over a few weeks under close supervision. doctor; patients should be warned about the possibility of relapse in the event of an abrupt termination.
Lithium may prolong the effect of neuromuscular blockers. Therefore, these drugs should always be administered with caution to patients receiving lithium (see Interactions).
Interactions Which drugs or foods can modify the effect of Carbolithium
Warning: Tell your doctor or pharmacist if you have recently taken or are taking any other medicines, even those without a prescription.
- Antipsychotics
Combination with clozapine, haloperidol or phenothiazines results in an increased risk of extrapyramidal adverse effects and possible neurotoxicity (combination to be avoided).
Combination with sulpiride causes an increased risk of extrapyramidal adverse effects (combination to be avoided).
The combination with sertindole and thioridazine causes an increased risk of ventricular arrhythmias. The combination with haloperidol can cause an encephalopathic syndrome; such an event (characterized by weakness, lethargy, fever, tremors, convulsions, confusion, extrapyramidal symptoms, leukocytosis), followed by irreversible brain damage, occurred in some patients treated with lithium at the same time as haloperidol. Although a causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established, patients undergoing this combination therapy should be carefully monitored in order to promptly reveal the first signs of neurotoxicity that require immediate discontinuation of treatment. There is a possibility of similar reactions with other antipsychotic medicines. Combination with antipsychotics can mask the symptoms of lithium toxicity, as they can prevent the onset of nausea, which is one of the first symptoms of lithium intoxication.
- Antidepressants
Combination with venlafaxine may result in increased serotonergic effects of lithium. Combination with selective serotonin reuptake inhibitors may result in an increased risk of central nervous system effects.
Combination with tricyclic antidepressants may result in an increased risk of lithium toxicity. In addition, symptoms such as diarrhea, confusion, tremor and agitation have been observed during combination therapy with lithium and selective serotonin reuptake inhibitors (SSRIs).
- Methyldopa
The association with methyldopa can cause an increase in lithium toxicity (neurotoxicity), even in the presence of lithemia values included in the therapeutic range.
- Antiepileptics
Phenomena of neurotoxicity have been observed following the combined administration of lithium with antiepileptics (in particular phenytoin, phenobarbital and carbamazepine).
- Alcohol
Concomitant alcohol intake can cause an increase in plasma lithium peak.
- ACE inhibitors
The combination with ACE inhibitors may cause a reduction in the elimination of lithium, with a consequent increase in lithemia.
- Antiarrhythmics
The concomitant use of amiodarone may cause the onset of ventricular arrhythmias (association not recommended).
- Angiotensin II receptor antagonists
Combination with angiotensin II receptor antagonists may result in a reduction in the elimination of lithium, with a consequent increase in lithemia.
- Calcium channel blockers
Concomitant use of calcium channel blockers (particularly verapamil and diltiazem) may lead to neurotoxicity, without increasing plasma lithium concentration, with symptoms such as ataxia, tremors, nausea, vomiting, diarrhea and tinnitus.
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, indomethacin, menefamic acid, naproxen, ketorolac, piroxicam and selective COX2 inhibitors) reduce the clearance of lithium, producing an increase in lithemia with a consequent increased risk of toxicity (association to be avoided).
During concomitant administration of nimesulide, lithemia should be carefully monitored.
- Steroidal Anti-Inflammatory Drugs (Corticosteroids)
The concomitant intake of corticosteroids causes salt and water retention, with a consequent increase in lithemia.
- Diuretics
The concomitant intake of loop diuretics and thiazides causes a reduction in the elimination of lithium with increased lithemia and risk of toxicity.
The association with osmotic diuretics, acetazolamide, amiloride and triamterene (particularly significant with amiloride and triamterene) can cause an increase in lithium excretion. In particular, the administration of a thiazide diuretic to patients stabilized on lithium therapy causes an increase in lithemia after 3-5 days.
Minor variations in lithemia have been observed with loop diuretics (furosemide, bumetanide and ethacrynic acid), however, patients receiving this combination should be carefully monitored.
Scientific evidence suggests that if a patient on lithium treatment is to initiate diuretic therapy, the lithium dose should be reduced by 25 to 50% and lithemia measured twice a week.
Indapamide and lithium should not be used concomitantly due to possible lithium toxicity resulting from reduced renal clearance. Potassium-sparing diuretics do not increase lithemia.
- Metoclopramide
Combination with metoclopramide causes an increased risk of extrapyramidal effects.
- Metronidazole
The association with metronidazole causes an increase in lithemia.
- Aminophylline and Mannitol
The association with aminophylline and mannitol leads to a decrease in lithemia.
Decreased plasma concentration and increased urinary excretion of lithium have been observed following combination therapy with chlorpromazine, acetazolamide, xanthines, urea and alkalizing agents such as sodium bicarbonate.
Significant increases in coffee consumption can lead to decreases in plasma lithium concentration.
Lithium may prolong the effect of neuromuscular blockers. Therefore these drugs should be administered with caution to patients on lithium therapy.
Warnings It is important to know that:
Patients discharged from health care facilities and their family members should be advised of the need for the following symptoms that are early indicators of drug toxicity: diarrhea, nausea, vomiting, abdominal pain, drowsiness, loss of muscle coordination, sedation, tremors weakness, muscle weakness, feeling of cold, should consult a doctor immediately and discontinue therapy.
It is the task of the specialist to inform the general practitioner of the treatment the patient is undergoing.
Stop taking lithium at least one week before starting electroconvulsive therapy (ECT) and resume treatment with lithium a few days after completion of the treatment.
In addition, lithium therapy should be discontinued 24 hours before major surgery, as reduced renal clearance associated with anesthesia can lead to lithium accumulation. Lithium therapy should be re-established as quickly as possible after surgery.
Pregnancy and breastfeeding
"Ask your doctor or pharmacist for advice before taking any medicine".
Lithium can cause fetal harm; lithium is excreted in breast milk. Therefore, the medicine is contraindicated in case of pregnancy, established or suspected, and during lactation.
Women of childbearing potential should have a pregnancy test before starting lithium salt therapy.
Women of childbearing age who are already on lithium salt therapy and wish to prepare for pregnancy must discontinue therapy by gradually decreasing the dose, under strict medical supervision, to avoid relapses (see Special warnings).
A few days after delivery it is advisable, always under close medical supervision, to resume therapy at low doses due to the increased risk of manic episodes and relapses in the post partum period, carefully avoiding breastfeeding.
Effects on ability to drive and use machines
Lithium can impair mental or physical capacity.
Carbolithium impairs the ability to drive or use machines.
Patients who conduct activities that require alertness should be aware of these effects.
Dosage and method of use How to use Carbolithium: Dosage
Dosage should be defined on an individual basis in relation to lithemia, patient tolerance and individual clinical response.
Adults and adolescents: 300 mg 2 to 6 times a day, given at regular intervals.
The maximum doses should be used in the attack therapy of severe forms, the minimum in prophylactic maintenance therapy.
It is always necessary to start therapy with low doses of the drug and titrate the dose according to the measurement of lithemia.
If lithium salt therapy is used in the age range of 12-18 years beyond the usual cautions and recommendations, the duration should be relatively short and continued only in the presence of unambiguous signs of clinical response to the drug.
Overdose What to do if you have taken an overdose of Carbolithium
In the event of suspected or presumed overdose, urgent determination of lithium plasma levels is required.
Most cases of lithium intoxication occur as a complication of long-term therapy and are caused by reduced excretion of the drug due to a number of factors including dehydration, deterioration of kidney function, infections and concomitant use of diuretics or NSAIDs (or other drugs - see Interactions).
Early clinical manifestations are nonspecific and may include apathy and restlessness that may be confused with mental status changes resulting from the patient's depressive pathology.
In case of severe intoxication, the main signs are cardiac, with alterations of the ECG, and neurological: dizziness, disturbed alertness, hyperreflexia, alert coma. The appearance of these symptoms requires immediate cessation of treatment, urgent control of lithemia, "increase in" excretion of lithium by increasing the alkalinity of the urine, osmotic diuresis (mannitol) and the addition of sodium chloride. Starting from a lithemia of 2.0 mEq / l, do not hesitate to perform hemodialysis or peritoneal dialysis. Close monitoring of white blood cell counts is advised in all cases of lithium overdose.
In case of accidental intake of more tablets than expected, the patient should contact their doctor and go to the nearest hospital with the medicine box.
WHAT TO DO IF YOU HAVE FORGOTTEN TO TAKE ONE OR MORE DOSES
If you have forgotten to take a dose, notify your doctor immediately.
Do not take two doses together.
EFFECTS DUE TO THE SUSPENSION OF THE TREATMENT
Although there is no clear evidence of withdrawal symptoms or rebound psychosis, abrupt discontinuation of lithium increases the risk of relapse. If treatment is to be discontinued, the dose should be gradually reduced over a few weeks under close supervision. doctor; patients should be warned about the possibility of relapse in the event of an abrupt termination.
IF YOU HAVE ANY DOUBT ABOUT THE USE OF CARBOLITHIUM, CONTACT YOUR DOCTOR OR PHARMACIST
Side Effects What are the side effects of Carbolithium
Like all medicines, CARBOLITHIUM can cause side effects, although not everybody gets them.
The onset and severity of undesirable effects are generally related to plasma levels, the rate at which plasma peak is reached and the different degree of sensitivity to lithium in the individual patient. Generally they are more severe the higher the plasma concentration. of the drug.
Litemia must therefore be monitored regularly during therapy to check that plasma levels associated with increased toxicity are not reached.
However, some patients may have lithemia levels that are considered toxic and show no signs of toxicity; others, on the contrary, can develop toxicity at therapeutic concentrations.
Generally, undesirable effects occur more frequently when plasma levels above 1.5 mEq / liter are reached, but may also occur for concentrations of 1 mEq / liter, particularly in the elderly. For these reasons, although plasma concentrations considered reasonably safe are within the range: 0.4-1.25 mEq / liter, it is preferable to keep the lithemia within the range 0.4-1 mEq / liter.
Slight hand tremors, polyuria and moderate thirst may occur at the start of therapy in the acute manic phase, and general malaise may occur during the first days of administration. These side effects generally disappear with continued treatment or with a temporary reduction in blood pressure. dose of drug If persist, treatment should be discontinued.
During the twenty-four hours following the first lithium administration, there may be an increase in urinary excretion of sodium, potassium and mineralocorticoids. Subsequently, potassium excretion normalizes and sodium retention may occur, due to increased secretion of aldosterone. , with the appearance of pretibial edema. These side effects also usually disappear within a few days. However, lithium therapy may result in a progressive decrease in the kidney's ability to concentrate urine with the possible onset of diabetes insipidus of nephrogenic origin.
Diarrhea, nausea, vomiting, abdominal pain, drowsiness, muscle weakness, motor incoordination, sedation, dry mouth, feeling cold, slow speech and nystagmus are the first signs of lithium intoxication and can occur at plasma levels below 2 mEq / liter. At higher levels of lithemia, symptoms can progress rapidly. Hyperreflexia, ataxia, dizziness, tinnitus, blurred vision and intense polyuria may occur. Plasma levels of lithium above 3 mEq / liter can produce a complex clinical picture, involving various organs and systems, leading to generalized convulsions, acute circulatory failure, stupor, coma and death.
The following undesirable effects have been reported during therapy:
Nervous system disorders: Absence, seizures, slurred speech, lightheadedness, dizziness, urinary and stool incontinence, drowsiness, fatigue, lethargy, psychomotor delays, confusion, restlessness, stupor, coma, tremors, muscle hyperirritability (contractions, movements clones of the legs), ataxia, choreoatotic movements, hyperexcitability of deep tendon reflexes, dry mouth
Cardiac disorders: cardiac arrhythmias, hypotension, peripheral circulation collapse, circulatory decompensation (rarely). Cases of prolongation of the QT interval, ventricular arrhythmias (such as torsade de pointes, ventricular tachycardia, ventricular fibrillation and cardiac arrest), cases of sudden death have been observed.
Renal and urinary disorders: albuminuria, oliguria, polyuria, glycosuria. Morphological changes with glomerular and interstitial fibrosis and atrophy of the nephrons have been found during prolonged lithium therapy.However, the same manifestations also occurred in manic-depressive patients never treated with lithium salts. The following side effects have been reported with an unknown frequency: benign / malignant kidney tumors (microcysts, oncocytoma or renal cell carcinoma of the collecting ducts (in long-term therapy)
Endocrine disorders: thyroid abnormalities: thyroid goiter and / or hypothyroidism (including myxedema). Rare cases of hyperthyroidism have been reported.
Gastrointestinal disorders: anorexia, nausea, vomiting and diarrhea.
Disorders of the blood and lymphatic system: a case of marked leukopenia (without appreciable changes in erythrocyte and platelet values) associated with an acute increase in litemia has been found in the literature. Furthermore, haematological alterations have been described in the case of long-term therapy with lithium.
Eye disorders: transient scotomas, visual disturbances.
Skin and subcutaneous tissue disorders: drying and thinning of the hair, alopecia, skin anesthesia, chronic folliculitis, exacerbation of psoriasis.
Metabolism and nutrition disorders: dehydration, weight loss.
Diagnostic tests: ECG and EEG variations. Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
See the expiry date printed on the package. The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Storage precautions
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.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
COMPOSITION
CARBOLITHIUM 150 mg:
One capsule contains:
active principle:
lithium carbonate (microencapsulated) 150 mg
excipients: magnesium stearate, gelatin, titanium dioxide (E171), indigo carmine (E 132), lactose, starch, methylcellulose.
CARBOLITHIUM 300 mg
One capsule contains:
active principle:
lithium carbonate (microencapsulated) 300 mg
excipients: magnesium stearate, gelatin, titanium dioxide (E171), indigo carmine (E132), methylcellulose.
PHARMACEUTICAL FORM AND CONTENT
Hard capsules. Box of 50 capsules of 150 mg
Hard capsules. Box of 50 capsules of 300 mg
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
CARBOLITHIUM HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One capsule contains:
active principle: lithium carbonate (microencapsulated) 150/300 mg.
For the full list of excipients, see 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsules.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Prophylaxis and treatment of states of excitement in manic and hypomanic forms and states of depression or chronic depressive psychosis of manic-depressive psychosis. Cluster headache
only in subjects who do not respond to other therapy, due to the low therapeutic index of lithium carbonate.
04.2 Posology and method of administration
Dosage should be defined on an individual basis in relation to lithemia, patient tolerance and individual clinical response.
Adults and adolescents: 300 mg 2 to 6 times a day, given at regular intervals. The maximum doses should be used in the attack therapy of severe forms, the minimum in prophylactic maintenance therapy.
It is always necessary to start therapy with low doses of the drug and titrate the dose according to the measurement of lithemia.
If lithium salt therapy is used in the age range of 12-18 years beyond the usual cautions and recommendations, the duration should be relatively short and continued only in the presence of unambiguous signs of clinical response to the drug.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients. Lithium salts are contraindicated in:
• heart disease,
• kidney failure,
• severe state of debilitation,
• increased sodium depletion,
• concomitant treatment with diuretics,
• ascertained or presumed pregnancy and lactation (see section 4.6).
The safety and efficacy of lithium salts in children under the age of 12 has not yet been established, therefore their use in such patients is not recommended, unless otherwise advised by the specialist.
04.4 Special warnings and appropriate precautions for use
Lithium salts have a low therapeutic index (narrow therapeutic / toxic ratio) and therefore should not be prescribed if their blood concentration cannot be controlled. It is always necessary to start therapy with low doses of the drug and titrate the dose according to the measurement of lithemia.
At the beginning of the therapy it is advisable to carry out the first determination of the lithemia upon reaching the steady state, ie after 4-8 days of the beginning of the therapy itself, on a blood sample taken 10-12 hours after the last administration.
Then repeat the lithemia measurement every week until the dosage remains constant for another four weeks, and then every three months. Dose adjustments should be made to keep lithemia in the 0.4-1 mEq / liter range.
Plasma concentrations between 0.8 and 1 mEq / liter are usually required for the treatment of acute mania.
Recurrence prevention is generally achieved with plasma concentrations ranging from 0.6 to 0.75 mEq / liter, but some patients are also controlled by lower concentrations of 0.4-0.6 mEq / liter.
It is necessary to monitor the lithemia and the clinical status of the patient after each dose increase and to carry out constant checks during the entire duration of therapy and in particular in the case of intercurrent diseases (including urinary tract infections), alternation of manic and depressive phases, introduction of new drugs, and changes in the diet with changes in the intake of salts and liquids. The bioavailability varies greatly in the different preparations: replacing one preparation with another requires the same precautions as in the beginning of treatment, careful monitoring of lithemia, consequent dose adjustments and the physician's assessment of the patient's clinical status.
Prior to initiating therapy with lithium salts it is advisable to evaluate cardiac, renal and thyroid function. These tests must be repeated periodically during therapy.
Pre-existing mild thyroid disorders are not necessarily a contraindication to lithium treatment; where hypothyroidism exists, thyroid function must be controlled both during the attack phase and during maintenance. In case of manifestation of hypothyroidism during therapy, it is advisable to carry out a "suitable replacement therapy with thyroid hormones.
Renal and thyroid function should be checked every 6-12 months in stable regimens (unless otherwise prescribed).
During lithium therapy, patients should undergo regular blood count monitoring; lithium therapy should be used with caution in patients with cardiovascular disease or a family history of QT interval prolongation.
Lithium therapy must not be initiated in patients with renal insufficiency (see section 4.3). During lithium salt therapy, gradual or sudden changes in renal function, even if within normal limits, indicate the need for review of treatment. Cases of microcysts, oncocytomas and renal cell carcinoma of the collecting ducts have been reported in patients with severe renal impairment treated with lithium for more than 10 years (see section 4.8).
Lithium salt therapy is not recommended in patients with Addison's disease or other conditions associated with sodium depletion and in severely debilitated or dehydrated patients.
Lithium toxicity is increased by sodium depletion.
A decrease in lithium tolerability can be caused by body dehydration (profuse sweating, diarrhea, vomiting); in these cases, patients should be advised to increase the administration of salts and liquids and to notify the physician. In the event that the aforementioned disorders are accompanied by an "infection with high temperature, a temporary reduction in the dose or interruption of the treatment is recommended, always under strict medical supervision.
Reduced renal lithium excretion has been observed in patients with cystic fibrosis. Particular caution in determining the lithium dose must be taken in patients with myasthenia gravis to avoid exacerbation of the disease.
Given the teratogenic potential of lithium, it is recommended in fertile women to carry out a pregnancy test before starting therapy (see sections 4.3 and 4.6).
Patients discharged from health care facilities and their family members should be advised of the need for the following symptoms that are early indicators of drug toxicity: diarrhea, nausea, vomiting, abdominal pain, drowsiness, loss of muscle coordination, sedation, tremors weakness, muscle weakness, feeling of cold, should consult a doctor immediately and discontinue therapy.
It is the task of the specialist to inform the general practitioner of the treatment the patient is undergoing.
Stop taking lithium at least one week before starting electroconvulsive therapy (ECT) and resume treatment with lithium a few days after completion of the treatment.
In addition, lithium therapy should be discontinued 24 hours before major surgery, as reduced renal clearance associated with anesthesia can lead to lithium accumulation. Lithium therapy should be re-established as quickly as possible after surgery.
Although there is no clear evidence of withdrawal symptoms or rebound psychosis, abrupt discontinuation of lithium increases the risk of relapse. If treatment is to be discontinued, the dose should be gradually reduced over a few weeks under close supervision. doctor; patients should be warned about the possibility of relapse in the event of an abrupt termination.
Lithium can prolong the effect of neuromuscular blockers. Therefore these drugs should always be administered with caution to patients who are administered lithium (see section 4.5).
04.5 Interactions with other medicinal products and other forms of interaction
• Antipsychotics
Combination with clozapine, haloperidol or phenothiazines results in an increased risk of extrapyramidal adverse effects and possible neurotoxicity (combination to be avoided).
Combination with sulpiride causes an increased risk of extrapyramidal adverse effects (combination to be avoided).
The combination with sertindole and thioridazine causes an increased risk of ventricular arrhythmias. The combination with haloperidol can cause an encephalopathic syndrome; such an event (characterized by weakness, lethargy, fever, tremors, convulsions, confusion, extrapyramidal symptoms, leukocytosis), followed by irreversible brain damage, occurred in some patients treated with lithium at the same time as haloperidol. Although a causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established, patients undergoing this combination therapy should be carefully monitored in order to promptly reveal the first signs of neurotoxicity that require immediate discontinuation of treatment. There is a possibility of similar reactions with other antipsychotic medicines. Combination with antipsychotics can mask the symptoms of lithium toxicity, as they can prevent the onset of nausea, which is one of the first symptoms of lithium intoxication.
• Antidepressants
Combination with venlafaxine may result in increased serotonergic effects of lithium. Combination with selective serotonin reuptake inhibitors may result in an increased risk of central nervous system effects.
Combination with tricyclic antidepressants may result in an increased risk of lithium toxicity. In addition, symptoms such as diarrhea, confusion, tremor and agitation have been observed during combination therapy with lithium and selective serotonin reuptake inhibitors (SSRIs).
• Methyldopa
The association with methyldopa can cause an increase in lithium toxicity (neurotoxicity), even in the presence of lithemia values included in the therapeutic range.
• Antiepileptics
Phenomena of neurotoxicity have been observed following the combined administration of lithium with antiepileptics (in particular phenytoin, phenobarbital and carbamazepine).
• Alcohol
Concomitant alcohol intake can cause an increase in plasma lithium peak.
• ACE inhibitors
The combination with ACE inhibitors may cause a reduction in the elimination of lithium, with a consequent increase in lithemia.
• Antiarrhythmics
The concomitant use of amiodarone may cause the onset of ventricular arrhythmias (association not recommended).
• Angiotensin II receptor antagonists
Combination with angiotensin II receptor antagonists may result in a reduction in the elimination of lithium, with a consequent increase in lithemia.
• Calcium antagonists
Concomitant use of calcium channel blockers (particularly verapamil and diltiazem) may lead to neurotoxicity, without increasing plasma lithium concentration, with symptoms such as ataxia, tremors, nausea, vomiting, diarrhea and tinnitus.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, indomethacin, menefamic acid, naproxen, ketorolac, piroxicam and selective COX2 inhibitors) reduce the clearance of lithium, producing an increase in lithemia with a consequent increased risk of toxicity (association to be avoided).
During concomitant administration of nimesulide, lithemia should be carefully monitored.
• Steroidal Anti-Inflammatory Drugs (Corticosteroids):
The concomitant intake of corticosteroids causes salt and water retention, with a consequent increase in lithemia.
• Diuretics
The concomitant intake of loop diuretics and thiazides causes a reduction in the elimination of lithium with increased lithemia and risk of toxicity.
The association with osmotic diuretics, acetazolamide, amiloride and triamterene (particularly significant with amiloride and triamterene) can cause an increase in lithium excretion.
In particular, the administration of a thiazide diuretic to patients stabilized on lithium therapy causes an increase in lithemia after 3-5 days.
Minor variations in lithemia have been observed with loop diuretics (furosemide, bumetanide and ethacrynic acid), however, patients receiving this combination should be carefully monitored.
Scientific evidence suggests that if a patient on lithium treatment is to initiate diuretic therapy, the lithium dose should be reduced by 25 to 50% and lithemia measured twice a week.
Indapamide and lithium should not be used concomitantly due to possible lithium toxicity resulting from reduced renal clearance.
Potassium-sparing diuretics do not increase lithemia.
• Metoclopramide
Combination with metoclopramide causes an increased risk of extrapyramidal effects.
• Metronidazole:
The association with metronidazole causes an increase in lithemia
• Aminophylline and Mannitol:
The association with aminophylline and mannitol leads to a decrease in lithemia.
Decreased plasma concentration and increased urinary excretion of lithium have been observed following combination therapy with chlorpromazine, acetazolamide, xanthines, urea and alkalizing agents such as sodium bicarbonate.
Significant increases in coffee consumption can lead to decreases in plasma lithium concentration.
Lithium may prolong the effect of neuromuscular blockers. Therefore these drugs should be administered with caution to patients on lithium therapy.
04.6 Pregnancy and lactation
Lithium can cause fetal harm; lithium is excreted in breast milk.
Therefore, the medicine is contraindicated in case of pregnancy, established or suspected, and during lactation.
Women of childbearing potential should have a pregnancy test before starting lithium salt therapy.
Women of childbearing age who are already on lithium salt therapy and wish to prepare for pregnancy must interrupt the therapy by gradually decreasing the dose, under strict medical supervision, to avoid the occurrence of relapses (see section 4.4).
A few days after delivery it is advisable, always under close medical supervision, to resume therapy at low doses due to the increased risk of manic episodes and relapses in the post partum period, carefully avoiding breastfeeding.
04.7 Effects on ability to drive and use machines
Lithium can impair mental or physical capacity.
Carbolithium impairs the ability to drive or use machines. Warn patients about activities that require alertness.
04.8 Undesirable effects
The onset and severity of undesirable effects are generally related to plasma levels, the rate at which plasma peak is reached and the different degree of sensitivity to lithium in the individual patient. Generally they are more severe the higher the plasma concentration. of the drug.
Litemia must therefore be monitored regularly during therapy to check that plasma levels associated with increased toxicity are not reached.
However, some patients may have lithemia levels that are considered toxic and show no signs of toxicity; others, on the contrary, can develop toxicity at therapeutic concentrations.
Generally, undesirable effects occur more frequently when plasma levels above 1.5 mEq / liter are reached, but may also occur for concentrations of 1 mEq / liter, particularly in the elderly. For these reasons, although plasma concentrations considered reasonably safe are within the range: 0.4-1.25 mEq / liter, it is preferable to keep the lithemia within the range 0.4-1 mEq / liter.
Slight hand tremors, polyuria and moderate thirst may occur at the start of therapy in the acute manic phase, and general malaise may occur during the first days of administration. These side effects generally disappear with continued treatment or with a temporary reduction in blood pressure. dose of drug If persist, treatment should be discontinued.
During the twenty-four hours following the first lithium administration, there may be an increase in urinary excretion of sodium, potassium and mineralocorticoids. Subsequently, potassium excretion normalizes and sodium retention may occur, due to increased secretion of aldosterone. , with the appearance of pretibial edema. These side effects also usually disappear within a few days. However, lithium therapy may lead to a progressive decrease in the kidney's ability to concentrate urine with the possible onset of diabetes insipidus of nephrogenic origin.
Diarrhea, nausea, vomiting, abdominal pain, drowsiness, muscle weakness, motor incoordination, sedation, dry mouth, feeling cold, slow speech and nystagmus are the first signs of lithium intoxication and can occur at plasma levels below 2 mEq / liter. At higher levels of lithemia, symptoms can progress rapidly. Hyperreflexia, ataxia, dizziness, tinnitus, blurred vision and intense polyuria may occur. Plasma levels of lithium above 3 mEq / liter can produce a complex clinical picture, involving various organs and systems, leading to generalized convulsions, acute circulatory failure, stupor, coma and death.
The following undesirable effects have been reported during therapy:
Nervous system disorders: absences, seizures, speech difficulties, lightheadedness, dizziness, incontinence of urine and faeces, drowsiness, fatigue, lethargy, psychomotor delays, confusion, restlessness, stupor, coma, tremors, muscle hyperirritability (contractions, clonic movements of the legs) , ataxia, choreoatotic movements, hyperexcitability of deep tendon reflexes, dry mouth.
Cardiac pathologies: cardiac arrhythmias, hypotension, peripheral circulation collapse, circulatory decompensation (rarely). Cases of prolongation of the QT interval, ventricular arrhythmias (such as torsade de pointes, ventricular tachycardia, ventricular fibrillation and cardiac arrest), cases of sudden death have been observed.
Renal and urinary disorders: albuminuria, oliguria, polyuria, glycosuria. Morphological changes with glomerular and interstitial fibrosis and atrophy of the nephrons have been found during prolonged lithium therapy. However, the same manifestations also occurred in manic-depressive patients never treated with lithium salts. They have been reconfirmed with an fThe following undesirable effects are not known: benign / malignant kidney tumors (microcysts, oncocytoma or renal cell carcinoma of the collecting ducts (in long-term therapy) (see section 4.4).
Endocrine pathologies: thyroid abnormalities: thyroid goiter and / or hypothyroidism (including myxedema). Rare cases of hyperthyroidism have been reported.
Gastrointestinal disorders: anorexia, nausea, vomiting and diarrhea.
Disorders of the blood and lymphatic system: in the literature, a case of marked leukopenia (without appreciable changes in the values of erythrocytes and platelets) associated with an acute increase in litemia has been found. Furthermore, haematological alterations have been described in the case of long-term therapy with lithium.
Eye disorders: transient scotomas, visual disturbances.
Skin and subcutaneous tissue disorders: drying and thinning of the hair, alopecia, skin anesthesia, chronic folliculitis, exacerbation of psoriasis.
Metabolism and nutrition disorders: dehydration, weight loss.
Diagnostic tests: ECG and EEG variations.
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili
04.9 Overdose
In the event of suspected or presumed overdose, urgent determination of lithium plasma levels is required.
Most cases of lithium intoxication occur as a complication of a therapy
long term and is caused by a reduced excretion of the drug due to a number of factors including dehydration, deterioration of renal function, infections and concomitant use of diuretics or NSAIDs (or other drugs - see section 4.5).
Early clinical manifestations are nonspecific and may include apathy and restlessness that may be confused with mental status changes resulting from the patient's depressive pathology. In case of severe intoxication , the main signs are cardiac, with ECG alterations, and neurological: dizziness, disturbed alertness, hyperreflexia, alert coma. The appearance of these symptoms requires immediate cessation of treatment, urgent control of lithemia, increased "lithium excretion by increasing the alkalinity of the urine, osmotic diuresis (mannitol) and" the addition of sodium chloride. Starting from a lithemia of 2.0 mEq / l do not hesitate to perform a hemodialysis or peritoneal dialysis. Careful monitoring of the leukocyte count is recommended in all cases of lithium overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Therapeutic category: antipsychotics - lithium.
ATC code: NO5AN.
Lithium is a monovalent cation that belongs to the group of alkali metals. Lithium possesses numerous pharmacological effects and, although the mechanism of action is not fully known, it possesses antimanic and antidepressant activity and is effective in the prophylaxis and therapy of cluster headaches. The mechanisms of action of lithium probably responsible for its action mood modulators include: i) regulation of the release of some neurotransmitters, such as serotonin, noradrenaline and dopamine; ii) interference with the activation of trimeric G proteins (Gs and Gi); iii) the reduction of the activation of the polyphosphoinositide signaling pathway, through the inhibition of the enzyme inositol-1-phosphatase; iv) the "inhibition of the" activity "of some enzymes, such as protein kinase C (PKC) and glycogen synthase kinase 3 (GSK3), involved in the regulation of numerous cellular activities, including gene transcription v) the regulation of" activity of transcription factors and vi) the increase of the expression of the antiapoptotic protein bcl2 (neuroprotective effect).
Furthermore, lithium modulates some hormonal responses mediated by the enzymes adenylate cyclase and phospholipase C, thus interfering with the activity of the vasopression ADH (reduction of the kidney's ability to concentrate urine) and of the thyroid stimulating hormone. , TSH (interference with thyroid function).
05.2 Pharmacokinetic properties
Lithium ions are rapidly absorbed from the gastrointestinal tract. The plasma half-life is approximately 24 hours. Increases in the plasma half-life have been reported in the elderly and in subjects with renal impairment. Excretion is mainly renal (90%). Effective plasma concentrations are between 0.4 and 1 mEq / liter. It is recommended not to exceed a lithemia of 1 mEq / liter. Steady state is obtained between 5 ° and "8th day. Lithium crosses the placental barrier and passes into breast milk.
The lithemia must not exceed 1mEq / liter. Concentrations from 1.5 to 2.5 mEq / liter have proved capable of producing toxic phenomena. At concentrations above 2.5 mEq / l there is severe intoxication. At concentrations above 3.5 mEq / l, lethal intoxications occur. The acute lethal dose of lithium varies but is generally associated with a lithemia greater than 3.5 mEq / L. The concomitant consumption of alcohol can cause an increase in the plasma lithium peak.
Bioavailability varies greatly in different preparations: replacing one preparation with another requires the same precautions as for starting treatment.
05.3 Preclinical safety data
Teratogenicity was observed after lithium treatment in lower mammals, including mice. On the contrary, studies in rabbits and monkeys have not shown any induced teratogenic effects
from lithium. In man, the first evidence of the effects of lithium on the fetus derives from the International Lithium Newborn Registry (1973-1975). Of the 225 registered infants, 25 (11.1%) were reported with malformations, of which 18 (8%) ) affected the cardiovascular system
Cardiovascular abnormalities included Ebstein's disease, a rare malformation of the
Tricuspid valve with secondary anomalies of the right ventricle and atrium. The data from the Registry suggest an incidence of Ebstein's disease of 1% among children exposed to lithium corresponding to a value between 200 and 400 times higher than normal. , subsequent work suggests that the Registry's retrospective data overestimate the true incidence of lithium teratogenicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Carbolithium 150 mg: magnesium stearate, gelatin, titanium dioxide (E 171), indigo carmine (E132), lactose, starch, methylcellulose.
Carbolithium 300 mg: magnesium stearate, gelatin, titanium dioxide (E 171), indigo carmine (E132), methylcellulose.
06.2 Incompatibility
See par. 4.5
06.3 Period of validity
5 years.
06.4 Special precautions for storage
No special storage precautions are required.
06.5 Nature of the immediate packaging and contents of the package
Box of 50 capsules of 150 mg in blisters. Box of 50 capsules of 300 mg in blisters
06.6 Instructions for use and handling
07.0 MARKETING AUTHORIZATION HOLDER
Teva Italia S.r.l. - Via Messina, 38 - 20154 Milan
08.0 MARKETING AUTHORIZATION NUMBER
Carbolithium 150 mg hard capsules - 50 capsules AIC 024597015
Carbolithium 300 mg hard capsules - 50 capsules AIC 024597039
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 24/03/1982 Renewal: June 2010
10.0 DATE OF REVISION OF THE TEXT
November 2015
