Active ingredients: Digoxin
LANOXIN 0.0625 mg - Tablets
LANOXIN 0.125 mg - Tablets
LANOXIN 0.250 mg - Tablets
LANOXIN 0.5 mg / 2 ml - Solution for injection
LANOXIN 0.05 mg / ml - Syrup
Why is Lanoxin used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Cardiac therapy - digitalis glycosides.
THERAPEUTIC INDICATIONS
LANOXIN is indicated in:
- Treatment of chronic heart failure with prevalent systolic dysfunction. Its therapeutic effects are more evident in patients with ventricular dilatation. Digoxin is particularly indicated when heart failure is accompanied by atrial fibrillation.
- Treatment of chronic atrial fibrillation and atrial flutter in order to contain the ventricular response rate.
Contraindications When Lanoxin should not be used
Digoxin is contraindicated in patients with hypersensitivity to the active substance, to other digitalis glycosides or to any of the excipients. Digoxin is contraindicated in intermittent complete heart block or second degree atrioventricular block, especially if there is a history of StokesAdams attacks. Digoxin is contraindicated in arrhythmias caused by cardioactive glycoside intoxication. Digoxin is contraindicated in supraventricular arrhythmias. associated with accessory atrioventricular pathways, as in Wolff-Parkinson-White syndrome, unless the electrophysiological characteristics of the accessory pathways, and the possible adverse effects of digoxin on these characteristics, have been adequately evaluated.
If there is evidence of an accessory pathway or suspicion that it is present, without a history of previous supraventricular arrhythmias, digoxin is still contraindicated.
Digoxin is contraindicated in ventricular tachycardia and ventricular fibrillation.
Digoxin is contraindicated in obstructive hypertrophic cardiomyopathy, unless there is concomitant atrial fibrillation or heart failure, but even then great caution is required in the use of digoxin.
For the content in ethyl alcohol (see paragraph "Special warnings") LANOXIN Syrup must not be administered during pregnancy, in patients suffering from hepatic diseases, epilepsy, alcoholism, injuries or brain diseases.
Precautions for use What you need to know before taking Lanoxin
Digoxin intoxication can trigger arrhythmias, some of which may resemble those for which the drug is indicated. For example, atrial tachycardia with variable atrioventricular block requires great attention because clinically the rhythm is similar to atrial fibrillation.
Many of the benefits of digoxin in arrhythmias arise from some degree of atrioventricular conduction block.
However, when an incomplete atrioventricular block already exists, the effects of its rapid progression must be expected. In case of complete block the idioventricular escape rhythm can be suppressed.
In some cases of sino-atrial disorders (eg, Sinus Node disease), digoxin can cause or exacerbate sinus bradycardia, or cause sinoatrial block.
Administration of digoxin in the period immediately following a myocardial infarction is not contraindicated. However, the use of inotropic drugs in some patients in this setting may lead to an undesirable increase in myocardial oxygen demand and ischaemia, and some retrospective follow-up studies suggest that digoxin is associated with an increased risk of death. consideration should be given to the possibility of arrhythmias in patients who, following myocardial infarction, may be hypokalaemic and susceptible to haemodynamic instability.
Limitations subsequently imposed on direct cardioversion must also be taken into account.
Digoxin treatment should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.
Digoxin can rarely trigger vasoconstriction and should therefore be avoided in patients with myocarditis.
Patients with beriberi heart disease may not respond adequately to digoxin if pre-existing thiamine deficiency has not been treated concomitantly.
Digoxin should not be used in constrictive pericarditis unless used to control ventricular rate during atrial fibrillation or to improve systolic dysfunction.
Digoxin improves exercise tolerance in patients with left ventricular systolic dysfunction and normal sinus rhythm.
This may or may not be associated with an improvement in the haemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is more evident at rest, less evident under exertion.
Use of therapeutic doses of digoxin may result in prolonged PR interval and lowering of the ST segment of the ECG. Digoxin may induce false positive changes in the ST-T segment of the ECG during exercise testing. These electrophysiological effects reflect the expected effects of the drug and are not indicative of toxicity.
In cases where cardiac glycosides have been taken within the previous two weeks, a patient's starting dose recommendations should be reviewed and dose reduction recommended.
Dosage recommendations should be reviewed if patients are elderly or there are other reasons why renal clearance of digoxin is reduced. A reduction in both the initial and maintenance dose should be considered.
In patients treated with digoxin, serum electrolytes and renal function should be monitored periodically by serum creatinine concentrations; the frequency of the checks depends on the clinical situation.
Determination of serum digoxin concentrations can be very helpful in making a decision for further digoxin administration, but other glycosides and other endogenous substances, similar digoxin, may cross-react in the assay giving false positive results.
Detections made while temporarily stopping digoxin treatment may be more appropriate.
Intramuscular administration is painful and is associated with muscle necrosis.
This route of administration cannot be recommended.
Rapid intravenous injection can cause vasoconstriction resulting in hypertension and / or reduced coronary flow.
Slow intravenous administration is therefore important in cases of hypertensive heart failure and acute myocardial infarction.
Patients with severe respiratory disease may have increased myocardial sensitivity to digitalis glycosides.
Hypokalaemia sensitizes the myocardium to the action of cardioactive glycosides.
Hypoxia, hypomagnesaemia and marked hypercalcemia increase the sensitivity of the myocardium to cardioactive glycosides.
Administration of digoxin to patients with thyroid disease requires caution. Both the initial and maintenance dose of digoxin should be reduced in case of thyroid hypofunction.
In hyperthyroid conditions there is relative resistance to digoxin and doses may need to be increased.
During the treatment of thyrotoxicosis the dosage should be progressively reduced in relation to the improvement of thyrotoxicosis.
Patients with malabsorption syndrome or gastrointestinal reconstructions may require higher digoxin doses.
Direct electrical cardioversion
The risk of causing dangerous arrhythmias with direct electrical cardioversion is considerably increased in the presence of digitalis intoxication, and is proportional to the energy used for cardioversion.
For elective electrical cardioversion of a patient taking digoxin, the drug should be stopped 24 hours before cardioversion is performed.
In an emergency, such as in cardiac arrest, the cardioversion attempt should be made using the lowest effective energy.
Direct electrical cardioversion is not appropriate in the treatment of arrhythmias caused by cardiac glycosides.
Hypericum perforatum preparations should not be taken concomitantly with medicinal products containing oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin due to the risk of decreased plasma levels and decreased therapeutic efficacy of oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin (see Interactions with other medicinal products and other forms of interaction).
Interactions Which drugs or foods can modify the effect of Lanoxin
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
These may depend on effects on renal excretion, tissue binding, plasma protein binding, distribution within the body, intestinal absorption capacity and sensitivity to digoxin.
Considering the possibility of interactions when concomitant therapies are envisaged is the best precaution, and monitoring of serum digoxin values is recommended in case of doubt.
Digoxin, in combination with beta-blocking drugs, may increase atrioventricular conduction time.
Agents that cause hypokalaemia or intracellular potassium depletion may cause increased sensitivity to digoxin; these include: some diuretics, lithium salts, corticosteroids and carbenoxolone. Concomitant administration with diuretics such as loop diuretics or hydrochlorothiazide should occur. under close monitoring of serum electrolytes and renal function. Patients treated with digoxin are more susceptible to the effects of hyperkalaemia aggravated by suxamethonium. Calcium, particularly when administered rapidly intravenously, may induce severe arrhythmias in digitized patients.
Co-administration of lapatinib with oral digoxin resulted in an increase in digoxin AUC. Caution should be exercised when administering digoxin concomitantly with lapatinib.
Bupropion and its most important circulating metabolite, both with and without digoxin, stimulated OATP4C1-mediated transport of digoxin. Studies have suggested that binding of buproprion and its metabolites to OATP4C1 is likely to increase digoxin transport, and thus increase renal secretion of digoxin. Serum levels of digoxin can be INCREASED by concomitant administration of: amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone, macrolide antibiotics such as, for example. erythromycin and clarithromycin, tetracyclines (and possibly other antibiotics), gentamicin, itraconazole, quinine, trimethoprim, alprazolam, indomethacin and propantheline, nefazodone, atorvastatin, cyclosporine, epoprostenol (transient effect), tetanol receptor antagonist , ritonavir / ritonavir-containing regimens, taleprevir, dronedarone, ranolazine, telmisartan, lapatinib and ticagrelor.
Serum digoxin levels may be REDUCED by concomitant administration of: antacids, some volume laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoin Giovanni (Hypericum perforatum), bupropion and supplemental enteral nutrition.
Serum digoxin concentrations may be decreased by concomitant administration of Hypericum perforatum preparations. This is due to the induction of the enzymes responsible for drug metabolism and / or P-glycoprotein by Hypericum perforatum-based preparations which therefore should not be administered concomitantly with digoxin.
If a patient is concurrently taking Hypericum perforatum products, plasma digoxin levels should be monitored and therapy with Hypericum perforatum products discontinued.
Plasma digoxin levels may be increased with discontinuation of Hypericum perforatum. The digoxin dosage may need to be adjusted.
Calcium channel blocking agents can cause either an increase or no change in serum digoxin levels.
Verapamil, felodipine and tiapamil increase serum digoxin levels.
Nifedipine and diltiazem may or may not affect serum digoxin levels, while isradipine does not cause any changes. Calcium channel blockers themselves are known to have depressive effects on the conduction of the sinoatrial and atrioventricular node, particularly diltiazem and the verapamil.
Sympathomimetic drugs have positive chronotropic effects that can promote cardiac arrhythmias. They can also lead to hypokalaemia, which can lead to or worsen cardiac arrhythmias. Concomitant use of digoxin and sympathomimetics may increase the risk of cardiac arrhythmias.
Drugs that modify the vascular tone of afferent and efferent arterioles can impair glomerular filtration. Angiotensin converting enzyme inhibitor drugs (ACEIs), angiotensin receptor antagonists (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors did not significantly alter pharmacokinetics of digoxin and did not consistently alter pharmacokinetic parameters, however, these drugs may alter renal function in some patients, resulting in a secondary increase in digoxin levels.
Milrinone does not change the steady-state serum levels of digoxin.
In patients receiving diuretics and ACE inhibitors, or diuretics alone, discontinuation of digoxin resulted in clinical worsening.
Digoxin is a substrate of P-glycoprotein. Therefore, inhibitors of P-glycoprotein may increase blood concentrations of digoxin by increasing its absorption and / or reducing its renal clearance. Induction of P-glycoprotein may result in a decrease in digoxin concentration. in the blood.
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription
Warnings It is important to know that:
Ask your doctor or pharmacist for advice before taking any medicine
Fertility
There are no data available on the effect of digoxin on human fertility. No data on the teratogenic effects of digoxin are available.
Pregnancy
The use of digoxin during pregnancy is not contraindicated; although its dosage is less predictable in the pregnant woman than in the nonpregnant state, in some cases an increase of the dosage during pregnancy may be necessary. Contraindications "regarding the syrup formulation.
As with all drugs, use in pregnancy should only be considered when the expected therapeutic benefits to the mother outweigh any potential risk to the fetus.
Despite significant exposure to digitalis before birth, no relevant adverse events were observed in fetuses or neonates when maternal serum digoxin concentrations were maintained within the normal range.
Although it has been hypothesized that a direct effect of digoxin on the myometrium may result in the birth of relatively premature and low birth weight infants, a role of the underlying heart disease cannot be excluded.
The administration of digoxin to mothers has been used successfully to treat fetal tachycardia and congestive heart failure.
Undesirable effects affecting the fetus have been reported in mothers with digitalis intoxication.
Feeding time
Although digoxin is excreted in breast milk, the quantities of the drug are negligible and breastfeeding is not contraindicated.
Newborns and premature babies
In the newborn and in the preterm infant, the doses must be established taking into account a possible lower tolerance towards digitalis, in relation to a possible functional immaturity of the liver and kidney.
Effects on ability to drive or use machines
As cases of visual and CNS disturbances have been reported in patients receiving digoxin, patients should exercise caution before driving vehicles, operating machinery or engaging in hazardous activities.
Due to the presence of ethyl alcohol LANOXIN Syrup can reduce the ability to drive and operate on machinery.
Important information about some of the ingredients
LANOXIN Syrup contains methyl parahydroxybenzoate; this substance can cause allergic reactions (even delayed)
LANOXIN syrup contains sucrose, if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
The alcohol content in LANOXIN Syrup may modify or enhance the effects of other drugs.
100 ml of LANOXIN Syrup contain 10.5 ml of 96% ethyl alcohol.
1 ml of LANOXIN Syrup contains 0.105 ml of 96% ethyl alcohol: the maximum single dose used in adults and children over 10 years of age in rapid oral digitization corresponds to 2.52 g of alcohol.
In the case of rapid oral digitization in children over 10 years of age, the administration of LANOXIN Syrup involves the patient taking daily doses of alcohol greater than 3 g total.
In the case of rapid oral digitization in children under the age of 10, the administration of LANOXIN Syrup, on the other hand, involves the child taking daily doses of alcohol less than 3 g.
Therefore, the attention of the prescriber is drawn to the need to scrupulously evaluate, in the light of the individual clinical picture, the risk / benefit balance of rapid oral digitization against the potential negative effects linked to the presence of alcohol in the formulation.
LANOXIN tablets contain lactose; if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product
For those who carry out sporting activities
The use of medicines containing ethyl alcohol can determine a positive anti-doping test in relation to the alcohol concentration limits indicated by some sports federations.
Dosage and method of use How to use Lanoxin: Dosage
Digoxin dosage should be individually adjusted for each patient according to age, lean body weight and renal function.
The suggested doses are therefore intended as a general criterion only.
The difference in bioavailability between LANOXIN Injectable and oral formulations should be considered when switching from one formulation to another. For example, if patients switch from oral to intravenous formulation, the dose should be reduced by approximately 33%.
LANOXIN Syrup (0.05 mg / 1 ml), comes with a graduated dispenser which must be used to measure all doses
Monitoring
Serum concentrations of digoxin can be expressed in Conventional Units of nanograms / ml or SI units of nanomoles / l. To convert nanograms / ml to nanomoles / l, multiply nanograms / ml by 1.28.
Serum concentrations of digoxin can be determined with radioimmunoassays. The blood sample should be taken 6 hours or more after the last digoxin administration.
There are no strict guidelines on the "range" of serum concentrations which are most effective. Various post-hoc analyzes of heart failure patients in the Digitalis Investigation Group study showed that at low serum digoxin concentrations (0.5-0.9 nanograms / mL) the use of digoxin was associated with reductions in mortality and hospitalizations. Patients with higher serum digoxin levels (> 1 nanograms / mL) had a "higher incidence of morbidity and mortality, although digoxin reduces hospitalizations for heart failure at these concentrations." Therefore, the optimal minimum serum level of digoxin can be from 0.5 nanograms / ml (0.64 nanomol / l) to 1.0 nanograms / ml (1.28 nanomol / l).
Digoxin toxicity is most commonly associated with serum digoxin concentrations greater than 2 nanograms / mL. However, toxicity may occur with lower serum digoxin concentrations.
In deciding whether a patient's symptoms are due to digoxin, evaluation of the clinical status together with evaluation of serum potassium levels and thyroid function are important (see Overdose).
Other glycosides, including digoxin metabolites, may interfere with available assay methods and values that do not appear to be compatible with the patient's clinical status should always be cautiously evaluated.
As regards the use of the syrup formulation in children, see also the paragraph "Special warnings".
Populations
- Adults and children over 10 years old
Quick Oral Digitization:
If clinically appropriate, rapid digitization can be achieved in several ways, such as: 0.75-1.5 mg as a single dose.
When less urgency is required or there is a greater risk of toxicity (eg in the elderly), it is advisable to administer the total dose necessary for rapid oral digitization in divided doses at six-hour intervals, starting therapy with a first dose equal to half of the total dose. Clinical response should be checked prior to each further administration (see Precautions for use).
Slow oral digitization:
In some patients, for example those with mild heart failure, digitization may be achieved more slowly with doses of 0.25-0.75 mg per day, for one week, followed by an appropriate maintenance dose. Clinical response should be seen within one week.
The dosage of 0.25-0.75 mg per day is valid for patients under 70 years of age and / or with good renal function, while the dosage for slow oral digitization in patients over 70 years of age and / or with renal insufficiency it is 0.125 mg per day.
The choice between slow or rapid oral administration depends on the patient's clinical situation and the severity of the condition.
Parenteral loading dose
For use in patients who have not received cardiac glycosides within the previous two weeks.
The total loading dose of parenteral digoxin ranges from 0.5 to 1.0 mg, based on age, lean body mass and renal function. The total loading dose should be administered in divided doses, with approximately half of the total dose given as the first dose and further fractions at four to eight hour intervals. Clinical response should be assessed before each additional dose is given. Each dose should be administered as an intravenous infusion over 10 to 20 minutes ( see Dilution of Lanoxin Solution for Injection).
Maintenance dose:
The maintenance dose should be calculated based on the percentage of the digitization dose eliminated daily. The following formula is widely used in the clinic:
Ccr is the corrected creatinine clearance per 70 kg body weight or 1.73 m2 body surface area.
If only serum creatinine (Scr) is available, the Ccr (corrected for 70 kg body weight) can be calculated in humans as follows:
Note: where serum creatinine values are obtained in micromoles / l, these must be converted to mg / 100 ml (mg%) as follows:
Where 113.12 is the molecular weight of creatinine.
For women, this result must be multiplied by 0.85.
N.B. These formulas cannot be used for the calculation of creatinine clearance in children. In practice, most patients with heart failure will be maintained on 0.125-0.25 mg of digoxin per day; however, for those experiencing "increased sensitivity to the side effects of digoxin, a dose of 0.0625 mg per day (or less) may be sufficient."
Conversely, some patients may require a higher dose.
- Newborns, infants and children up to 10 years of age (if no cardiac glycosides have been given in the previous two weeks)
If cardiac glycosides have been administered in the two weeks prior to initiation of digoxin therapy, the optimal loading dose of digoxin should be expected to be less than recommended below.
In neonates, particularly if premature, renal clearance of digoxin is reduced and appropriate dose reductions should be made beyond what is recommended in the general dosing instructions. After the first neonatal period, children generally require proportionally larger doses than the adult based on weight and body surface area, as indicated in the following table. Children over 10 years of age require, based on their body weight, adult dosages.
Parenteral Loading Dose:
The intravenous loading dose in the groups indicated below should be done in accordance with the following posologies
The loading dose should be administered in divided doses with approximately half of the total dose administered as the first dose and further fractions of the total dose administered at 4-8 hour intervals, checking the clinical response before each subsequent dose is administered. Each dose should be administered by intravenous infusion (see Dilution) over a period of 10-20 minutes.
Oral Loading Dose:
Oral digitization must be done according to the following posologies:
The loading dose should be administered in divided doses with approximately half of the total dose administered as the first dose and further fractions of the total dose administered at 4-8 hour intervals, checking the clinical response before each subsequent dose is administered.
Maintenance:
The maintenance dose should be administered according to the following posology:
Preterm infants: Daily dose = 20% of the 24-hour loading dose (intravenous or oral)
Term infants and children up to 10 years of age; Daily dose = 25% of the 24-hour loading dose (intravenous or oral)
These dosage schedules are to be considered as guidelines and a careful clinical observation and a careful moni
- Senior citizens
The tendency to decreased renal function and reduced lean body mass in the elderly influences the pharmacokinetics of digoxin, so that elevated serum digoxin levels with associated toxicity may occur fairly quickly, unless digoxin doses lower than those are used. used in non-elderly patients. Serum digoxin levels should be monitored regularly, and hypokalaemia should be avoided.
- Dosage recommendations in specific patient groups
See "Precautions for use".
Instructions for Use
LANOXIN Syrup (0.05 mg / 1ml) comes with a graduated dispenser which must be used to measure all doses.
Dilution
LANOXIN Syrup must not be diluted.
Dilution of LANOXIN Solution for injection:
LANOXIN Solution for injection can be administered undiluted or diluted with a volume of diluent equal to or greater than 4 times the volume of LANOXIN. The use of a diluent volume of less than 4 times the volume of LANOXIN may lead to the precipitation of digoxin
LANOXIN Solution for injection, 250 micrograms per ml, when diluted in the ratio 1: 250 (e.g. a 2 ml ampoule containing 500 micrograms added to 500 ml of infusion solution) is compatible with the following infusion solutions and stable for up to 48 hours at room temperature (20-25 ° C):
- 0.9% weight / volume sodium chloride solution for intravenous infusion, B.P .;
- Solution for intravenous infusion of Sodium Chloride (0.18% weight / volume) and Glucose (4% weight / volume), B.P .;
- 5% weight / volume glucose solution for intravenous infusion, B.P.
Dilution must be performed under aseptic conditions, or immediately prior to use. Unused solution must be discarded.
Rapid intravenous injection can cause vasoconstriction resulting in hypertension and / or reduced coronary flow.
Slow intravenous administration is therefore important in cases of hypertensive heart failure and acute myocardial infarction.
Intramuscular administration is painful and is associated with muscle necrosis. This route of administration cannot be recommended.
Overdose What to do if you have taken too much Lanoxin
Symptoms and signs
Symptoms and signs of toxicity are generally similar to those described in the section "Undesirable effects" but may be more frequent and may be more severe.
Signs and symptoms of digoxin toxicity become more frequent at levels above 2.0 nanograms / ml (2.56 nanomoles / l), although considerable interindividual variability exists. However, in deciding whether a patient's symptoms are caused by digoxin, important factors to consider are the clinical picture, serum electrolyte levels, and thyroid function (see Dose, method and time of administration).
Adults
Clinical experience shows that an overdose of digoxin of 10 to 15 mg in adults without heart disease appears to be the dose that causes death in half of patients. If an adult without heart disease ingests a dose of digoxin greater than 25 mg, this results in death or progressive toxicity that responds only to treatment with digoxin specific antibody fragments (Fab).
Cardiac manifestations
Cardiac manifestations are the most frequent and severe signs of both acute and chronic toxicity. The peak of cardiac effects typically occurs 3 to 6 hours after overdose and may persist for the following 24 hours and beyond. Digoxin toxicity can result in almost any type of arrhythmia. Multiple rhythm disturbances are common in some patients. These include paroxysmal atrial tachycardia with variable atrioventricular (AV) block, accelerated junctional rhythm, slow atrial fibrillation (with limited ventricular rhythm variation), and bi-directional ventricular tachycardia.
Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy is also common.
Sinus bradycardia and other bradyarrhythmias are very common.
First, second, and third degree heart blocks and AV dissociation are also common.
Early toxicity can only manifest itself with prolongation of the PR interval.
Ventricular tachycardia can also be a manifestation of toxicity.
Cardiac arrest due to asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.
Acute massive digoxin overdose may result in mild to marked hyperkalaemia due to inhibition of the sodium-potassium (Na + -K +) pump. Hypokalaemia may contribute to toxicity (see Precautions for use).
Non-cardiac manifestations
Gastrointestinal symptoms are very common in both acute and chronic toxicity. Symptoms precede cardiac manifestations in about half of patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence of up to 80%. These symptoms generally present early in the course of an overdose.
Neurological and visual manifestations occur in both acute and chronic toxicity. Vertigo, various disorders of the Central Nervous System, fatigue and malaise are very common. The most frequent visual disturbance is an aberration in color vision (predominance of yellow-green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.
In case of chronic toxicity, non-specific extracardiac symptoms such as malaise and weakness may be predominant.
Pediatric population
In children aged 1 to 3 years without heart disease, clinical experience suggests that an overdose of 6 to 10 mg digoxin constitutes the dose that is fatal in half of patients.
If more than 10 mg of digoxin was ingested by a 1 to 3 year old child without heart disease, the outcome was always fatal when Fab antibody fragments were not used.
Most manifestations of toxicity in children occur during or immediately after the digoxin loading phase.
Cardiac manifestations
The same arrhythmias or combinations of arrhythmias that appear in adults can occur in children.
Sinus tachycardia, supraventricular tachycardia and rapid atrial fibrillation were observed less frequently in the pediatric population. Pediatric patients are more likely to have AV conduction disturbances or sinus bradycardia.
Ventricular ectopia is less common, however, ventricular ectopia, ventricular tachycardia and ventricular fibrillation have been reported in cases of massive overdose.
In neonates, sinus bradycardia or sinus arrest and / or prolonged P / R intervals are frequent signs of toxicity. Sinus bradycardia is common in infants and children. In older children, AV blocks are the most common conduction disturbances.
Any arrhythmia or abnormal cardiac conduction that occurs in children taking digoxin should be considered to be caused by digoxin until further evaluation shows otherwise.
Extracardiac manifestations
Frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, CNS and vision. However, nausea and vomiting are not common in infants and younger children.
In addition to the undesirable effects observed with recommended doses, overdose, weight loss in older patient groups, insufficient growth in neonates, abdominal pain due to mesenteric artery ischaemia, somnolence and behavioral disturbances have been reported. , including psychotic manifestations.
Treatment
If the intake was recent, such as in case of accidental or deliberate poisoning, the load available for absorption can be reduced by gastric lavage.
Gastric lavage increases vagal tone and can precipitate or worsen arrhythmias. Consider pretreatment with atropine if gastric lavage is performed. Treatment with antidigital antibody fragments usually renders gastric lavage unnecessary. In the rare cases where gastric lavage is indicated, it should only be performed by experienced individuals who have had appropriate training. Patients who have ingested large doses of digitalis should be treated with high-dose activated charcoal to prevent absorption and fix digoxin. in the intestine during enteroenteric recirculation.
If hypokalaemia is present it should be corrected with potassium supplements, either by mouth, or intravenously, depending on the urgency of the situation. In cases where a large amount of digoxin has been ingested, hyperkalaemia may be present. due to the release of potassium from the skeletal muscles.
Before administering potassium, in the event of a digoxin overdose, the serum potassium levels should be known.
Bradyarrhythmias may respond to atropine, but temporary regulation of the heart rhythm may be required. Ventricular arrhythmias may respond to lidocaine or phenytoin. Dialysis is not particularly effective in removing digoxin from the body under potentially dangerous toxic conditions For the life.
Digoxin-specific antibody fragments Fab constitute the specific treatment for digoxin-induced toxicity and are highly effective.
Rapid resolution of complications associated with severe digoxin, digitoxin, and related glycosides intoxication is determined by intravenous administration of digoxin-specific antibody (Fab) fragments of sheep origin. For details, consult the literature provided with the antibody fragments.
Side Effects What are the side effects of Lanoxin
In general, the undesirable effects of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Therefore, undesirable effects are less frequent when digoxin is used within the range of the recommended dose or therapeutic serum concentration and when particular attention is paid to concomitant treatment with other drugs and to the patient's condition.
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and
Very common, common and uncommon events are generally defined by clinical studies. The incidence of placebo was also considered. Adverse reactions identified through post-marketing surveillance have been classified as rare or very rare (including isolated cases).
Disorders of the blood and lymphatic system
Very rare: thrombocytopenia
Metabolism and nutrition disorders
Very rare: anorexia
Psychiatric disorders
Uncommon: depression
Very rare: psychosis, apathy, confusion
Central nervous system disorders
Common: central nervous system disorders, dizziness
Very rare: headache
Eye disorders
Common: visual disturbances (blurred or yellow vision)
Cardiac pathologies
Common: arrhythmia, conduction disturbance, bigeminy, trigeminy, PR prolongation, sinus bradycardia
Very rare: supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, premature ventricular contraction, ST segment elevation
Gastrointestinal disorders
Common: nausea, vomiting, diarrhea
Very rare: intestinal ischaemia, intestinal necrosis
Skin and subcutaneous tissue disorders
Common: urticarial or scarlet-like rash, which may be accompanied by marked eosinophilia
Diseases of the reproductive system and breast
Very rare: gynecomastia may occur in long-term administration
General disorders and administration site conditions
Very rare: fatigue, malaise, weakness
Reporting of side effects
If you get any side effects, including any possible side effects not listed in this leaflet, contact your doctor or pharmacist. 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
Expiry: see the expiry date indicated on the package.
Warning: do not use the medicine after the expiry date indicated on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Conservation rules
Tablets: store in the original container to keep it away from humidity and at a temperature not exceeding 30 ° C.
Syrup: keep in the outer packaging to keep it away from light and at a temperature not exceeding 25 ° C.
Solution for injection: Store in the outer carton to protect from light
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.
COMPOSITION
LANOXIN 0.0625 mg Tablets
One tablet contains:
Active ingredient: digoxin 0.0625 mg
Excipients: lactose, corn starch, rice starch, hydrolyzed corn starch, povidone, indigo carmine (E132), magnesium stearate.
LANOXIN 0.125 mg Tablets
One tablet contains:
Active ingredient: digoxin 0.125 mg
Excipients: lactose, corn starch, rice starch, hydrolyzed corn starch, magnesium stearate.
LANOXIN 0.250 mg Tablets
One tablet contains:
Active ingredient: digoxin 0.250 mg.
Excipients: lactose, corn starch, rice starch, hydrolyzed corn starch, magnesium stearate.
LANOXIN 0.5 mg / 2 ml Solution for injection
A 2ml vial contains:
Active ingredient: 0.5 mg digoxin
Excipients: ethyl alcohol, propylene glycol, citric acid, dibasic sodium phosphate, water for injections
LANOXIN 0.05 mg / ml Syrup
100 ml contain:
Active ingredient: digoxin 5 mg
Excipients: dibasic sodium phosphate, citric acid, methyl-parahydroxybenzoate, hydrogenated glucose syrup, quinoline yellow (E104), lime flavor, ethyl alcohol, propylene glycol, purified water.
PHARMACEUTICAL FORM AND CONTENT
Blister packs of 30 tablets of 0.0625 mg, 0.125 mg and 0.250 mg. Box of 6 ampoules of 0.5 mg / 2ml solution for injection. Bottle of 60 ml of 0.05 mg / ml syrup.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
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01.0 NAME OF THE MEDICINAL PRODUCT
LANOXIN TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
LANOXIN 0.0625 mg Tablets
One tablet contains:
Active ingredient: digoxin 0.0625 mg
LANOXIN 0.125 mg Tablets
One tablet contains:
Active ingredient: digoxin 0.125 mg
LANOXIN 0.250 mg Tablets
One tablet contains:
Active ingredient: digoxin 0.250 mg LANOXIN 0.5 mg / 2 ml Solution for injection A 2ml vial contains:
Active ingredient: 0.5 mg digoxin
LANOXIN 0.05 mg / ml Syrup
100 ml contain:
Active ingredient: digoxin 5 mg
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Tablets, solution for injection, syrup.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
LANOXIN is indicated in:
Treatment of chronic heart failure with prevalent systolic dysfunction. Its therapeutic effects are more evident in patients with ventricular dilatation. Digoxin is particularly indicated when heart failure is accompanied by atrial fibrillation.
Treatment of chronic atrial fibrillation and atrial flutter in order to contain the ventricular response rate.
04.2 Posology and method of administration
Dosage :
Digoxin dosage should be individually adjusted for each patient according to age, lean body weight and renal function.
The suggested doses are therefore intended as a general criterion only.
The difference in bioavailability between LANOXIN Injectable and oral formulations should be considered when switching from one formulation to another. For example, if patients switch from oral to intravenous formulation, the dose should be reduced by approximately 33%.
Monitoring
Serum concentrations of digoxin can be expressed in Conventional Units of nanograms / ml or SI units of nanomoles / l. To convert nanograms / ml to nanomoles / l, multiply nanograms / ml by 1.28.
Serum concentrations of digoxin can be determined with radioimmunoassays. The blood sample should be taken 6 hours or more after the last administration of digoxin. There are no strict guidelines on the "range" of serum concentrations that are most effective. Various post-hoc analyzes of heart failure patients in the Digitalis Investigation Group study showed that at low serum digoxin concentrations (0.5-0.9 nanograms / mL) the use of digoxin was associated with reductions in mortality and hospitalizations. Patients with higher serum digoxin levels (> 1 nanograms / mL) had a "higher incidence of morbidity and mortality, although at these concentrations digoxin reduces hospitalizations for heart failure. Therefore, the optimal minimum serum digoxin level. it can be from 0.5 nanograms / ml (0.64 nanomoles / l) to 1.0 nanograms / ml (1.28 nanomoles / l).
Digoxin toxicity is most commonly associated with serum digoxin concentrations greater than 2 nanograms / mL. However, toxicity may occur with lower serum digoxin concentrations.
In deciding whether the patient's symptoms are due to digoxin, evaluation of the clinical status together with evaluation of serum potassium levels and thyroid function are important (see section 4.9 Overdose).
Other glycosides, including digoxin metabolites, may interfere with available assay methods and values that do not appear to be compatible with the patient's clinical status should always be cautiously evaluated.
Populations
Adults and children over 10 years old.
Quick oral digitization :
If clinically appropriate, rapid digitization can be achieved in several ways, such as: 0.75-1.5 mg as a single dose.
When less urgency is required or there is a greater risk of toxicity (e.g. in the elderly), it is advisable to administer the total dose necessary for rapid oral digitization in divided doses at six-hour intervals, starting therapy with a first dose equal to half of the total dose.
The clinical response should be checked prior to each further administration (see section 4.4 Special warnings and precautions for use).
Slow oral digitization :
In some patients, for example those with mild heart failure, digitization may be achieved more slowly with doses of 0.25-0.75 mg per day, for one week, followed by an appropriate maintenance dose. Clinical response should be seen within one week.
The dosage of 0.25 - 0.75 mg per day is valid for patients under 70 years of age and / or with good renal function, while the dosage for slow oral digitization in patients over 70 years of age and / or with renal insufficiency it is 0.125 mg per day.
The choice between slow or rapid oral administration depends on the patient's clinical situation and the severity of the condition.
Parenteral loading dose :
For use in patients who have not received cardiac glycosides within the previous two weeks.
The total loading dose of parenteral digoxin ranges from 0.5 to 1.0 mg, based on age, lean body mass and renal function. The total loading dose should be administered in divided doses, with approximately half of the total dose given as the first dose and further fractions at four to eight hour intervals. Clinical response should be assessed before each additional dose is given. Each dose should be administered as an intravenous infusion over 10 to 20 minutes ( see Dilution of Lanoxin Solution for Injection).
Maintenance dose :
The maintenance dose should be calculated based on the percentage of the digitization dose eliminated daily. The following formula is widely used in the clinic:
Ccr is the corrected creatinine clearance per 70 kg body weight or 1.73 m2 body surface area. If only serum creatinine (Scr) is available, the Ccr (corrected for 70 kg body weight) can be calculated in humans as follows:
Note: where serum creatinine values are obtained in micromoles / l, these must be converted to mg / 100 ml (mg%) as follows:
Where 113.12 is the molecular weight of creatinine.
For women, this result must be multiplied by 0.85.
N.B.These formulas cannot be used for the calculation of creatinine clearance in children.
In practice, most patients with heart failure will be maintained on 0.125-0.25 mg of digoxin per day; however, for those experiencing increased sensitivity to digoxin side effects, a dose of 0.0625 mg per day (or less) may be sufficient. Conversely, some patients may require a higher dose.
Newborns, infants and children up to 10 years of age (if no cardiac glycosides have been given in the previous two weeks)
If cardiac glycosides have been administered in the two weeks prior to initiation of digoxin therapy, the optimal loading dose of digoxin should be expected to be less than recommended below.
In neonates, particularly if premature, renal clearance of digoxin is reduced and appropriate dose reductions should be made beyond what is recommended in the general dosing instructions.
After the first neonatal period, children generally require proportionally larger doses than the adult based on weight and body surface area, as indicated in the following table. Children over 10 years of age require, based on their body weight, adult dosages.
Parenteral loading dose :
The intravenous loading dose in the groups indicated below must be made according to the following posologies:
The loading dose should be administered in divided doses with approximately half of the total dose administered as the first dose and further fractions of the total dose administered at 4-8 hour intervals, checking the clinical response before each subsequent dose is administered. Each dose should be administered by intravenous infusion (see Dilution 6.6 Instructions for use and handling) over a period of 10-20 minutes.
Oral loading dose :
Oral digitization must be done according to the following posologies:
The loading dose should be administered in divided doses with approximately half of the total dose administered as the first dose and further fractions of the total dose administered at 4-8 hour intervals, checking the clinical response before each subsequent dose is administered.
Maintenance :
The maintenance dose should be administered according to the following posology: Preterm infants:
Daily dose = 20% of the 24-hour loading dose (intravenous or oral) Term infants and children up to 10 years;
Daily dose = 25% of the 24-hour loading dose (intravenous or oral)
These dosing regimens are intended as guidelines and "careful clinical observation and monitoring of serum digoxin levels (see Monitoring) should be used as a starting point for dose modification in these pediatric patient groups.
Senior citizens
The tendency to decreased renal function and reduced lean body mass in the elderly influences the pharmacokinetics of digoxin, so that elevated serum digoxin levels with associated toxicity may occur fairly quickly, unless digoxin doses lower than those are used. used in non-elderly patients. Serum digoxin levels should be monitored regularly, and hypokalaemia should be avoided.
Dosage recommendations in specific patient groups
See section 4.4 Special warnings and special precautions for use.
Method of administration :
LANOXIN Syrup (0.05 mg / 1 ml), comes with a graduated dispenser which must be used to measure all doses.
As regards the use of the syrup formulation in children, see also section 4.5 Interactions with other medicinal products and other forms of interaction.
LANOXIN Solution for injection
Rapid intravenous injection can cause vasoconstriction resulting in hypertension and / or reduced coronary flow.
Slow intravenous administration is therefore important in cases of hypertensive heart failure and acute myocardial infarction.
Intramuscular administration is painful and is associated with muscle necrosis. This route of administration cannot be recommended.
Dilution of LANOXIN Solution for injection:
LANOXIN Solution for injection can be administered undiluted or diluted with a volume of diluent equal to or greater than 4 times the volume of LANOXIN. The use of a volume of diluent less than 4 times the volume of LANOXIN may lead to precipitation of digoxin.
For instructions on dilution of the medicinal product before administration, see section 6.6 Special precautions for disposal and handling.
04.3 Contraindications
Digoxin is contraindicated in patients with hypersensitivity to the active substance, to other digitalis glycosides or to any of the excipients listed in section 6.1.
Digoxin is contraindicated in intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks.
Digoxin is contraindicated in arrhythmias caused by intoxication with cardiac glycosides.
Digoxin is contraindicated in supraventricular arrhythmias associated with accessory atrioventricular pathways, such as in Wolff-Parkinson-White syndrome, unless the electrophysiological characteristics of the accessory pathways, and the possible adverse effects of digoxin on these characteristics, have been adequately evaluated.
If there is evidence of an accessory pathway or suspicion that it is present, without a history of previous supraventricular arrhythmias, digoxin is still contraindicated.
Digoxin is contraindicated in ventricular tachycardia and ventricular fibrillation.
Digoxin is contraindicated in obstructive hypertrophic cardiomyopathy, unless there is concomitant atrial fibrillation or heart failure, but even then great caution is required in the use of digoxin.
For the content in ethyl alcohol (see section 4.5 Interactions with other medicinal products and other forms of interaction) LANOXIN Syrup must not be administered during pregnancy, in patients suffering from hepatic diseases, epilepsy, alcoholism, lesions or brain diseases.
04.4 Special warnings and appropriate precautions for use
Digoxin intoxication can trigger arrhythmias, some of which may resemble those for which the drug is indicated. For example, atrial tachycardia with variable atrioventricular block requires great attention because clinically the rhythm is similar to atrial fibrillation.
Many of the benefits of digoxin in arrhythmias arise from some degree of atrioventricular conduction block.
However, when an incomplete atrioventricular block already exists, the effects of its rapid progression must be expected. In case of complete block the idioventricular escape rhythm can be suppressed.
In some cases of sino-atrial disorders (eg in Sinus Node Disease), digoxin can cause or exacerbate sinus bradycardia, or cause sinoatrial block.
Administration of digoxin in the period immediately following a myocardial infarction is not contraindicated. However, the use of inotropic drugs in some patients in this setting may lead to an undesirable increase in myocardial oxygen demand and ischaemia, and some retrospective follow-up studies suggest that digoxin is associated with an increased risk of death. taking into account the possibility of arrhythmias in patients who, following myocardial infarction, may be hypokalaemic and susceptible to haemodynamic instability.
Limitations subsequently imposed on direct cardioversion must also be taken into account.
Digoxin treatment should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if there are no appropriate alternative treatments, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.
Digoxin can rarely trigger vasoconstriction and should therefore be avoided in patients with myocarditis.
Patients with beriberi heart disease may not respond adequately to digoxin if pre-existing thiamine deficiency has not been treated concomitantly.
Digoxin should not be used in constrictive pericarditis unless used to control ventricular rate during atrial fibrillation or to improve systolic dysfunction.
Digoxin improves exercise tolerance in patients with left ventricular systolic dysfunction and normal sinus rhythm.
This may or may not be associated with an improvement in the haemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is more evident at rest, less evident under exertion.
Use of therapeutic doses of digoxin may result in prolonged PR interval and lowering of the ST segment of the ECG. Digoxin may induce false positive changes in the ST-T segment of the ECG during exercise testing. These electrophysiological effects reflect the expected effects of the drug and are not indicative of toxicity.
In cases where cardiac glycosides have been taken within the previous two weeks, a patient's starting dose recommendations should be reviewed and dose reduction recommended. Dosage recommendations should be reviewed if patients are elderly or there are other reasons why renal clearance of digoxin is reduced. A reduction in both the initial and maintenance dose should be considered.
In patients treated with digoxin, serum electrolytes and renal function should be monitored periodically by serum creatinine concentrations; the frequency of the checks depends on the clinical situation.
Determination of serum digoxin concentrations can be very helpful in making a decision for further digoxin administration, but other glycosides and other endogenous substances, similar digoxin, may cross-react in the assay giving false positive results.
Detections made while temporarily stopping digoxin treatment may be more appropriate.
Patients with severe respiratory disease may have increased myocardial sensitivity to digitalis glycosides.
Hypokalaemia sensitizes the myocardium to the action of cardioactive glycosides.
Hypoxia, hypomagnesaemia and marked hypercalcemia increase the sensitivity of the myocardium to cardioactive glycosides.
Administration of digoxin to patients with thyroid disease requires caution. Both the initial and maintenance dose of digoxin should be reduced in case of thyroid hypofunction.
In hyperthyroid conditions there is relative resistance to digoxin and doses may need to be increased.
During the treatment of thyrotoxicosis the dosage should be progressively reduced in relation to the improvement of thyrotoxicosis.
Patients with malabsorption syndrome or gastrointestinal reconstructions may require higher digoxin doses.
Although many patients with chronic congestive heart failure benefit from acute administration of digoxin, there are some in which such administration does not lead to lasting haemodynamic improvements. It is therefore important to individually assess each patient's response when Lanoxin is continued long-term.
Electrical cardioversion
The risk of causing dangerous arrhythmias with direct electrical cardioversion is considerably increased in the presence of digitalis intoxication, and is proportional to the energy used for cardioversion.
For elective electrical cardioversion of a patient taking digoxin, the drug should be stopped 24 hours before cardioversion is performed.
In an emergency, such as in cardiac arrest, the cardioversion attempt should be made using the lowest effective energy.
Direct electrical cardioversion is not appropriate in the treatment of arrhythmias caused by cardiac glycosides.
Hypericum perforatum preparations should not be taken concomitantly with medicinal products containing oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin due to the risk of decreased plasma levels and decreased therapeutic efficacy of oral contraceptives, digoxin, theophylline, carbamazepine, phenobarbital, phenytoin (see Section 4.5. Interactions with other medicinal products and other forms of interaction).
Important information about some of the ingredients
The tablets of LANOXIN contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
LANOXIN syrup contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase isomaltase deficiency should not take this medicine.
LANOXIN syrup contains methyl parahydroxydobenzoato. Such a substance that can cause allergic reactions (even delayed).
100 ml of LANOXIN syrup contain 10.5 ml of 96% ethyl alcohol. 1 ml of LANOXIN Syrup contains 0.105 ml of 96% ethyl alcohol: the maximum single dose used in adults and children over 10 years of age in rapid oral digitization corresponds to 2.52 g of alcohol.
In the case of rapid oral digitization in children over 10 years of age, the administration of LANOXIN Syrup involves the patient taking daily doses of alcohol greater than 3 g total.
In the case of rapid oral digitization in children under the age of 10, the administration of LANOXIN Syrup, on the other hand, involves the child taking daily doses of alcohol less than 3 g.
Therefore, the attention of the prescriber is drawn to the need to scrupulously evaluate, in the light of the individual clinical picture, the risk / benefit balance of rapid oral digitization against the potential negative effects linked to the presence of alcohol in the formulation.
04.5 Interactions with other medicinal products and other forms of interaction
These may depend on effects on renal excretion, tissue binding, plasma protein binding, distribution within the body, intestinal absorption capacity, degree of P-glycoprotein activity and sensitivity to digoxin.
Considering the possibility of interactions when concomitant therapies are envisaged is the best precaution, and monitoring of serum digoxin values is recommended in case of doubt.
Digoxin, in combination with beta-blocking drugs, may increase atrioventricular conduction time.
Agents that cause hypokalaemia or intracellular potassium depletion may cause increased sensitivity to digoxin; these include: some diuretics, lithium salts, corticosteroids and carbenoxolone. Concomitant administration with diuretics, such as loop diuretics or hydrochlorothiazide, should be done under close monitoring of serum electrolytes and renal function.
Patients treated with digoxin are more susceptible to the effects of hyperkalaemia aggravated by suxamethonium.
Calcium, particularly when administered rapidly intravenously, can induce severe arrhythmias in digitized patients.
Co-administration of lapatinib with oral digoxin resulted in an increase in digoxin AUC. Caution should be exercised when administering digoxin concomitantly with lapatinib.
Bupropion and its most important circulating metabolite, both with and without digoxin, stimulated OATP4C1-mediated transport of digoxin. Studies have suggested that binding of buproprion and its metabolites to OATP4C1 is likely to increase digoxin transport, and thus increase renal secretion of digoxin.
Serum levels of digoxin can be INCREASED by concomitant administration of: amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone, macrolide antibiotics such as, for example. erythromycin and clarithromycin, tetracyclines (and possibly other antibiotics), gentamicin, itraconazole, quinine, trimethoprim, alprazolam, indomethacin and propantheline, nefazodone, atorvastatin, cyclosporine, epoprostenol (transient effect), tetanol receptor antagonist , ritonavir / ritonavir-containing regimens, taleprevir, dronedarone, ranolazine, telmisartan, lapatinib and ticagrelor.
Serum digoxin levels may be REDUCED by concomitant administration of: antacids, some volume laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoine and nutrition supplemental enteral.
Serum digoxin concentrations may be decreased by concomitant administration of Hypericum perforatum preparations. This is due to the induction of the enzymes responsible for drug metabolism and / or P-glycoprotein by Hypericum perforatum-based preparations which therefore should not be administered concomitantly with digoxin. If a patient is taking Hypericum-based products at the same time. perforatum plasma levels of digoxin should be monitored and therapy with Hypericum perforatum products should be discontinued. Plasma digoxin levels may be increased upon discontinuation of Hypericum perforatum. Digoxin dosing may need to be adjusted. adjustment.
Calcium channel blocking agents can cause either an increase or no change in serum digoxin levels. Verapamil, felodipine and tiapamil increase serum digoxin levels. Nifedipine and diltiazem may or may not affect serum digoxin levels, while isradipine does not cause any changes. Calcium channel blockers themselves are known to have depressive effects on the conduction of the sinoatrial and atrioventricular node, particularly diltiazem and the verapamil.
Sympathomimetic drugs have positive chronotropic effects that can promote cardiac arrhythmias. They can also lead to hypokalaemia, which can lead to or worsen cardiac arrhythmias. Concomitant use of digoxin and sympathomimetics may increase the risk of cardiac arrhythmias.
Drugs that modify the vascular tone of afferent and efferent arterioles can impair glomerular filtration.
Angiotensin converting enzyme inhibitor drugs (ACEIs), angiotensin receptor antagonists (ARBs), nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors did not significantly alter pharmacokinetics of digoxin and have not consistently altered pharmacokinetic parameters. However, these drugs may alter renal function in some patients, resulting in a secondary increase in digoxin levels. Milrinone does not change serum levels at the same time. steady state of digoxin.
In patients receiving diuretics and ACE inhibitors, or diuretics alone, discontinuation of digoxin resulted in clinical worsening.
Digoxin is a substrate of P-glycoprotein. Therefore, P-glycoprotein inhibitors may increase blood concentrations of digoxin by increasing its absorption and / or reducing its renal clearance (see section 5.2, Pharmacokinetic Properties). Induction of P-glycoprotein may result in a decrease in the concentration of digoxin in the blood.
The alcohol content in LANOXIN Syrup may modify or enhance the effects of other drugs.
04.6 Pregnancy and lactation
Fertility
There are no data available on the effect of digoxin on human fertility. No data on the teratogenic effects of digoxin are available.
Pregnancy
The use of digoxin during pregnancy is not contraindicated; although its dosage is less predictable in the pregnant woman than in the nonpregnant state, in some cases an increase of the dosage during pregnancy may be necessary. See, however, section 4.3 Contraindications regarding the syrup formulation.
As with all drugs, use in pregnancy should only be considered when the expected therapeutic benefits to the mother outweigh any potential risk to the fetus.
Despite significant exposure to digitalis before birth, no relevant adverse events were observed in fetuses or neonates when maternal serum digoxin concentrations were maintained within the normal range.
Although it has been hypothesized that a direct effect of digoxin on the myometrium may result in the birth of relatively premature and low birth weight infants, a role of the underlying heart disease cannot be excluded.
The administration of digoxin to mothers has been used successfully to treat fetal tachycardia and congestive heart failure.
Undesirable effects affecting the fetus have been reported in mothers with digitalis intoxication.
Feeding time
Although digoxin is excreted in breast milk, the quantities of the drug are negligible and breastfeeding is not contraindicated.
Newborns and premature babies
In the newborn and in the preterm infant, the doses must be established taking into account a possible lower tolerance towards digitalis, in relation to a possible functional immaturity of the liver and kidney.
04.7 Effects on ability to drive and use machines
As cases of visual and CNS disturbances have been reported in patients receiving digoxin, patients should exercise caution before driving vehicles, operating machinery or engaging in hazardous activities.
Due to the presence of ethyl alcohol LANOXIN Syrup can reduce the ability to drive and operate on machinery.
04.8 Undesirable effects
Summary of the safety profile
In general, the undesirable effects of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Therefore, undesirable effects are less frequent when digoxin is used within the range of the recommended dose or therapeutic serum concentration and when particular attention is paid to concomitant treatment with other drugs and to the patient's condition.
List / Table of Adverse Reactions
Adverse reactions are listed below by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and
Disorders of the blood and lymphatic system
Very rare: thrombocytopenia
Metabolism and nutrition disorders
Very rare: anorexia
Psychiatric disorders
Uncommon: depression
Very rare: psychosis, apathy, confusion
Central nervous system disorders
Common: central nervous system disorders, dizziness
Very rare: headache
Eye disorders
Common: visual disturbances (blurred or yellow vision)
Cardiac pathologies
Common: arrhythmia, conduction disturbance, bigeminy, trigeminy, PR prolongation, sinus bradycardia
Very rare: supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, premature ventricular contraction, ST segment elevation
Gastrointestinal disorders
Common: nausea, vomiting, diarrhea
Very rare: intestinal ischaemia, intestinal necrosis
Skin and subcutaneous tissue disorders
Common: urticarial or scarlet-like rash, which may be accompanied by marked eosinophilia
Diseases of the reproductive system and breast
Very rare: gynecomastia may occur in long-term administration
General disorders and administration site conditions
Very rare: fatigue, malaise, weakness
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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
04.9 Overdose
Symptoms and signs
Symptoms and signs of toxicity are generally similar to those described in section 4.8 "Undesirable effects" but may be more frequent and may be more severe.
Signs and symptoms of digoxin toxicity become more frequent at levels above 2.0 nanograms / ml (2.56 nanomoles / l), although considerable interindividual variability exists. However, in deciding whether a patient's symptoms are caused by digoxin, important factors to consider are the clinical picture, serum electrolyte levels and thyroid function (see 4.2 Posology and method of administration). In patients undergoing hemodialysis, digoxin use is associated with increased mortality; patients with low pre-dialysis potassium concentrations are those at greatest risk.
Adults
Clinical experience shows that an overdose of digoxin of 10 to 15 mg in adults without heart disease appears to be the dose that causes death in half of patients. If an adult without heart disease ingests a dose of digoxin greater than 25 mg, this results in death or progressive toxicity that responds only to treatment with digoxin specific antibody fragments (Fab).
Cardiac manifestations
Cardiac manifestations are the most frequent and severe signs of both acute and chronic toxicity. The peak of cardiac effects typically occurs 3 to 6 hours after overdose and may persist for the following 24 hours and beyond. Digoxin toxicity can result in almost any type of arrhythmia. Multiple rhythm disturbances are common in some patients. These include paroxysmal atrial tachycardia with variable atrioventricular (AV) block, accelerated junctional rhythm, slow atrial fibrillation (with limited ventricular rhythm variation), and bi-directional ventricular tachycardia.
Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmias. Bigeminy or trigeminy are also common. Sinus bradycardia and other bradyarrhythmias are very common.
First, second, and third degree heart blocks and AV dissociation are also common. Early toxicity can only manifest itself with prolongation of the PR interval.
Ventricular tachycardia can also be a manifestation of toxicity.
Cardiac arrest due to asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.
Acute massive digoxin overdose may result in mild to marked hyperkalaemia due to inhibition of the sodium-potassium (Na + -K +) pump. Hypokalaemia may contribute to toxicity (see 4.4 Special warnings and special precautions for use. ).
Non-cardiac manifestations
Gastrointestinal symptoms are very common in both acute and chronic toxicity. Symptoms precede cardiac manifestations in about half of patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence of up to 80%. These symptoms usually present early in the course of an overdose.
Neurological and visual manifestations occur in both acute and chronic toxicity. Vertigo, various disorders of the Central Nervous System, fatigue and malaise are very common. The most frequent visual disturbance is an aberration in color vision (predominance of yellow-green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.
In case of chronic toxicity, non-specific extracardiac symptoms such as malaise and weakness may be predominant.
Pediatric population
In children aged 1 to 3 years without heart disease, clinical experience suggests that an overdose of 6 to 10 mg digoxin constitutes the dose that is fatal in half of patients.
If more than 10 mg of digoxin was ingested by a 1 to 3 year old child without heart disease, the outcome was always fatal when Fab antibody fragments were not used.
Most manifestations of toxicity in children occur during or immediately after the digoxin loading phase.
Cardiac manifestations
The same arrhythmias or combinations of arrhythmias that appear in adults may occur in children. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation have been observed less frequently in the pediatric population.
Pediatric patients are more likely to have AV conduction disturbances or sinus bradycardia.
Ventricular ectopia is less common, however, ventricular ectopia, ventricular tachycardia and ventricular fibrillation have been reported in cases of massive overdose.
In neonates, sinus bradycardia or sinus arrest and / or prolonged P / R intervals are frequent signs of toxicity. Sinus bradycardia is common in infants and children. In older children, AV blocks are the most common conduction disturbances.
Any arrhythmia or abnormal cardiac conduction that occurs in children taking digoxin should be considered to be caused by digoxin until further evaluation shows otherwise.
Non-cardiac manifestations
Frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, CNS and vision. However, nausea and vomiting are not common in infants and younger children.
In addition to the undesirable effects observed with recommended doses, overdose, weight loss in older patient groups, insufficient growth in neonates, abdominal pain due to mesenteric artery ischaemia, somnolence and behavioral disturbances have been reported. , including psychotic manifestations.
Treatment
If the intake was recent, such as in case of accidental or deliberate poisoning, the load available for absorption can be reduced by gastric lavage. Gastric lavage increases vagal tone and can precipitate or worsen arrhythmias. Consider pretreatment with atropine if gastric lavage is performed. Treatment with antidigital antibody fragments usually renders gastric lavage unnecessary. In the rare cases where gastric lavage is indicated, it should only be performed by experienced people who have had appropriate training.
Patients who have ingested large doses of digitalis should be treated with high-dose activated charcoal to prevent absorption and fix digoxin in the intestine during enteroenteric recirculation.
If hypokalaemia is present it should be corrected with potassium supplements, either by mouth, or intravenously, depending on the urgency of the situation. In cases where a large amount of digoxin has been ingested, hyperkalaemia may be present. due to the release of potassium from the skeletal muscles.
Before administering potassium, in the event of a digoxin overdose, the serum potassium levels should be known.
Bradyarrhythmias may respond to atropine, but temporary regulation of the heart rhythm may be required. Ventricular arrhythmias may respond to lidocaine or phenytoin.
Dialysis is not particularly effective in removing digoxin from the body in potentially life-threatening toxic conditions.
Digoxin-specific antibody fragments Fab constitute the specific treatment for digoxin-induced toxicity and are highly effective.
Rapid resolution of complications associated with severe digoxin, digitoxin, and related glycosides intoxication is determined by intravenous administration of digoxin-specific antibody (Fab) fragments of sheep origin. For details, consult the literature provided with the antibody fragments.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiac therapy - digitalis glycosides. ATC code: C01AA05.
Mechanism of action
Digoxin increases myocardial contractility by direct action. The effect is proportional to the dose in the lower values of the therapeutic range and some effect occurs with rather low dosages. This also occurs in normal myocardium, although this is totally devoid of physiological benefits.
The main action of digoxin is specifically to inhibit adenosine triphosphatase and therefore the sodium-potassium exchange (Na + -K +), the altered distribution of ions across the membrane determines as a consequence an increased influx of calcium ions and therefore an increased availability of calcium to the moment of excitation-contraction.
The potency of digoxin can therefore be considerably increased when the concentration of extracellular potassium is low, having the opposite effect in conditions of hyperkalaemia.
Digoxin has the same fundamental effect of inhibiting the Na + -K + exchange in the cells of the autonomic nervous system, stimulating them to indirectly influence cardiac activity. The increases in vagal efferent impulses cause a reduction in sympathetic tone and a decrease in the conduction speed of the "impulse through the atria and the atrioventricular node. Thus the most important beneficial effect of digoxin is the reduction of the ventricular rhythm.
Pharmacodynamic effects
Changes in cardiac contractility also result indirectly from changes in venous compliance, through changes in the activity of the autonomic nervous system and through direct venous stimulation. The interactions between direct and indirect action determine the total circulatory response, which is not the same for all In the presence of certain supraventricular arrhythmias, neurologically mediated slowing of AV conduction is critical. The degree of neurohormonal activation that occurs in patients with heart failure is associated with clinical worsening and an increased risk of death. Digoxin reduces activation. of both the sympathetic nervous system and the renin-angiotensin system, regardless of its inotropic actions and can therefore favorably affect survival.
It remains unclear whether this effect is achieved through a mechanism of direct inhibition of the sympathetic nervous system or by baroreflex resensitization.
05.2 Pharmacokinetic properties
Absorption
Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5-30 minutes and reaches a maximum in 1-5 hours. After oral administration, digoxin is absorbed in the stomach and upper small intestine. When digoxin is taken after meals, the rate of absorption is slowed but the total amount of digoxin absorbed is generally unchanged. When taken with fiber-rich meals, however, the amount absorbed following an oral dose may be reduced.
Following oral administration the onset of effect occurs in 0.5-2 hours and reaches its maximum at 2-6 hours. The bioavailability of orally administered digoxin is approximately 63% with the tablets and 75% with the oral solution.
Distribution
The initial distribution of digoxin from the central to the peripheral compartment usually lasts 6-8 hours. There follows a more gradual decline in serum digoxin concentrations which depends on the elimination of digoxin from the body. The volume of distribution is high (Vdss = 510 liters in healthy volunteers) indicating that digoxin is extensively bound to tissues. The highest concentrations of digoxin are found in the heart, liver and kidneys; the concentration in the heart is equal to 30 times that present in the systemic circulation. Although the concentration present in skeletal muscle is considerably lower, this reserve cannot be neglected as skeletal muscles account for 40% of the total body weight. Of the small fraction of digoxin present in plasma about 25% is bound to proteins.
Biotransformation
The main metabolites of digoxin are dihydrodigoxin and digoxigenin.
Elimination
The main route of elimination is renal excretion in the form of unchanged drug.
Digoxin is a substrate of P-glycoprotein. As an efflux protein located on the apical membrane of enterocytes, P-glycoprotein can limit the absorption of digoxin. P-glycoprotein present in proximal renal tubules appears to play an important role in renal elimination of digoxin (See 4.5 Interactions).
Following intravenous administration to healthy volunteers, 60-75% of a dose of digoxin is recovered unchanged in the urine over the next six days. Total body clearance of digoxin has been shown to be directly related to renal function and the percent daily elimination is therefore a function of creatinine clearance which can be estimated from stable serum creatinine.
In a population of healthy control volunteers, total and renal clearance of digoxin were found to be 193 ± 25 ml / min and 152 ± 24 ml / min.
In a small percentage of individuals, digoxin administered orally is converted to cardioinactive reduction products (digoxin reduction products or DRPs) by colonic bacteria in the gastrointestinal tract. In these subjects more than 40% of the dose can be excreted in the urine in the form of DRPs.
The renal clearance of the two major metabolites, dihydrodigoxin and aigoxygenin, was found to be 79 ± 13 mL / min and 100 ± 26 mL / min, respectively. However, in most cases, the major route of elimination of digoxin is renal excretion in the form of unchanged drug.
The terminal elimination half-life of digoxin in patients with normal renal function is 30-40 hours.
Since much of the drug is tissue bound rather than circulating, digoxin is not effectively removed from the body during the cardio-pulmonary bypass.Furthermore, only about 3% of a dose of digoxin is removed from the body during a 5-hour hemodialysis.
Special patient populations
Newborns, infants and children up to 10 years
During the neonatal period, renal clearance of digoxin is reduced and appropriate dose adjustments should therefore be made. This is particularly pronounced in premature babies since renal clearance reflects the maturation of renal function. Digoxin clearance was 65.6 ± 30 ml / min / 1.73 m2 at 3 months of age compared to only 32 ± 7 ml / min / 1.73 m2 at 1 week of life.
Outside the postnatal period, children generally require proportionately higher doses than adults based on body weight and body surface area.
Kidney failure
The terminal elimination half-life of digoxin in patients with impaired renal function is prolonged and may be around 100 hours in anuric patients.
05.3 Preclinical safety data
Mutagenesis.
The only data available derive from "in vitro" studies (Ames test and lymphoma in mice) in which dioxin does not show genotoxic potential.
Cangerogenesis
No data are available on the carcinogenic potential of digoxin.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
LANOXIN 0.0625 mg Tablets:
lactose, corn starch, rice starch, hydrolyzed corn starch, indigo carmine (E132), povidone, magnesium stearate
LANOXIN 0.125mg Tablets, LANOXIN 0.250mg Tablets:
lactose, corn starch, rice starch, hydrolyzed corn starch, magnesium stearate
LANOXIN 0.5 mg / 2 ml Solution for injection:
ethyl alcohol, propylene glycol, citric acid, dibasic sodium phosphate, water for injections
LANOXIN 0.05 mg / ml Syrup:
dibasic sodium phosphate, citric acid, methyl parahydroxybenzoate, hydrogenated glucose syrup, quinoline yellow (E 104), lime flavor, ethyl alcohol, propylene glycol, purified water
06.2 Incompatibility
No data are available.
06.3 Period of validity
Tablets and Solution for Injection: 3 years
Syrup: 18 months.
06.4 Special precautions for storage
Tablets: store in the original container to keep it away from humidity and at a temperature not exceeding 30 ° C.
Syrup: keep in the outer packaging to keep it away from light and at a temperature not exceeding 25 ° C.
Solution for injection: Store in the outer carton to protect from light.
06.5 Nature of the immediate packaging and contents of the package
LANOXIN 0.0625 mg Tablets: Blister packs of 30 tablets of 0.0625 mg
LANOXIN 0.125 mg Tablets: Blister packs of 30 tablets of 0.125 mg
LANOXIN 0.250 mg Tablets: Blister packs of 30 tablets of 0.250 mg
LANOXIN 0.5 mg / 2 ml Solution for injection: Box of 6 ampoules of 2 ml
LANOXIN 0.05 mg / ml Syrup
60 ml bottle with child resistant closure with attached graduated dispenser
06.6 Instructions for use and handling
LANOXIN Syrup (0.05 mg / 1ml) comes with a graduated dispenser which must be used to measure all doses.
Dilution
LANOXIN Syrup must not be diluted.
Dilution of LANOXIN Solution for injection :
LANOXIN Solution for injection can be administered undiluted or diluted with a volume of diluent equal to or greater than 4 times the volume of LANOXIN. The use of a volume of diluent less than 4 times the volume of LANOXIN may lead to precipitation of digoxin.
LANOXIN Solution for injection, 250 mcg per ml, when diluted in the ratio 1: 250 (e.g. a 2 ml vial containing 500 mcg added to 500 ml of infusion solution) is compatible with the following infusion solutions and stable for up to 48 hours at room temperature (20-25 ° C):
• 0.9% weight / volume sodium chloride solution for intravenous infusion, B.P .;
• Solution for intravenous infusion of Sodium Chloride (0.18% weight / volume) and Glucose (4% weight / volume), B.P .;
• 5% weight / volume Glucose solution for intravenous infusion, B.P.
Dilution must be performed under aseptic conditions, or immediately prior to use. Unused solution must be discarded.
07.0 MARKETING AUTHORIZATION HOLDER
Aspen Pharma Trading Limited
3016 Lake Drive,
Citywest Business Campus, Dublin 24, Ireland
08.0 MARKETING AUTHORIZATION NUMBER
LANOXIN 0.0625 mg Tablets: A.I.C. 015724065
LANOXIN 0.125 mg Tablets: A.I.C. 015724038
LANOXIN0,250 mg Tablets: A.I.C. 015724026
LANOXIN 0.5 mg / 2 ml Solution for injection: A.I.C. 015724053
LANOXIN 0.05 mg / ml Syrup: A.I.C. 015724077
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
LANOXIN 0.0625 mg Tablets: Apr. 1986 / May. 2010
LANOXIN 0.125 mg Tablets: Jun 1981 / May 2010
LANOXIN 0.250 mg Tablets: Nov. 1975 / May. 2010
LANOXIN 0.5 mg / 2 ml Solution for injection: Oct 1959 / May 2010
LANOXIN 0.05 mg / ml Syrup: Sept. 2003 / May. 2010
