Package Insert: Information for the User

Digoxina Kern Pharma 0.25 mg Tablets

Digoxina Kern Pharma belongs to the group of medications known as cardiac glycosides. Its active ingredient is digoxin, which increases the force of contraction of the heart muscle by specific inhibition of an enzyme called sodium/potassium-dependent adenosine triphosphatase.

This medication is indicated for the treatment of certain heart problems, including:

• “chronic heart failure” where the main problem is “systolic dysfunction” (alterations in heart contraction),
• when heart failure is accompanied by “atrial fibrillation” (abnormal heart rhythms originating from the upper chambers of the heart (atria) that do not contract uniformly),
• in the treatment of certain “supraventricular arrhythmias” (abnormal heart rhythms originating from the atria), especially atrial flutter (rapid heart rhythm) and atrial fibrillation (abnormal heart rhythms originating from the upper chambers of the heart (atria) that do not contract uniformly), the main benefit being the reduction of ventricular rate (slower heart rhythm).

Do not take Digoxina Kern Pharma

• if you are allergic to digoxin, other digitalis glycosides, or any of the other components of this medication,
• if your doctor has told you that you have any of the following heart problems:
• • intermittent heart block or second-degree atrioventricular block (abnormalities in the transmission of the electrical impulse between the upper and lower chambers of the heart), especially if you have a history of a heart condition called Stokes-Adams syndrome,
  • certain types of supraventricular arrhythmias, such as in the case of Wolff-Parkinson-White syndrome (a hereditary heart disease),
  • ventricular tachycardia (rapid heart rate originating in the ventricles) or in ventricular fibrillation (abnormal heart rhythm that can be fatal),
  • hypertrophic obstructive cardiomyopathy (a disease in which there is excessive growth of the heart muscle),
• if you have arrhythmias caused by intoxication with other cardiac glycosides (heart medications),
• if you know or suspect the presence of an accessory pathway (abnormal electrical communication between the atria and ventricles) and do not have a history of previous supraventricular arrhythmias, this medication is equally contraindicated.

Warnings and precautions

This medication should be used exclusively under the supervision and control of a doctor. Consult your doctor or pharmacist before starting to take this medication in any of the following cases:

• if you have recently had a myocardial infarction, digoxin should be taken with caution,
• if you are being treated with diuretics and an ACE inhibitor (heart and hypertension medications), or only diuretics, as when digoxin is discontinued, your condition may worsen,
• if you have taken cardiac glycosides (heart medications) two weeks before starting treatment with digoxin, your doctor should consider reducing the initial dosage,
• if you are administered to elderly patients or in patients with decreased renal function, your doctor should consider reducing both the initial and maintenance dosages,
• when you are already being treated with digoxin, your doctor should monitor your serum electrolytes and renal function (concentration of a certain enzyme called serum creatinine) periodically. The frequency of monitoring will depend on the severity of the case,
• if you have severe respiratory disease, as the heart muscle may be more sensitive to digoxin,
• if you have low potassium levels in the blood, as this makes the heart muscle more sensitive to the actions of digoxin,
• if you have hypoxia (low oxygen levels in the blood), hypomagnesemia (low magnesium levels in the blood), and marked hypercalcemia (high calcium levels in the blood), as these increase the sensitivity of the heart muscle to digoxin,
• if you have thyroid disease, you should exercise caution when using this medication. The initial and maintenance dosages of digoxin should be reduced when thyroid function is deficient. In the case of hyperthyroidism (high levels of thyroid hormone in the blood), there is a relative resistance to digoxin (less activity of this medication) and you may need to increase the dosage. During the treatment of thyrotoxicosis (excess of thyroid hormones), the dosage should be reduced as the disease is controlled,
• patients with malabsorption syndrome (difficulty of the body to absorb correctly vitamins, minerals, and other nutrients from food) or gastrointestinal reconstructions may require higher doses of digoxin.

Use of Digoxina Kern Pharma with other medications

Inform your doctor or pharmacist that you are using or have recently used or may need to use any other medication.

Agents that cause hypokalemia or intracellular potassium deficiency may increase sensitivity to Digoxina; these include some diuretics (medications to facilitate the elimination of liquids), lithium salts, corticosteroids (anti-inflammatory medications), and carbenoxolone (medication for the treatment of mouth sores).

The levels of digoxin in the blood may increase with the concurrent administration of the following medications:

• Amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone (heart medications).
• Calcium channel blockers and ACE inhibitors (hypertension medications).
• Erythromycin, tetracycline, gentamicin, itraconazole, trimethoprim (antibiotics).
• Quinine (medication for the treatment of malaria).
• Alprazolam, lithium salts (medication for depression).
• Difenoxilate with atropine (association of medications used as antidiarrheal).
• Indomethacin.
• Propantelina (medication for the treatment of ulcers).

The levels of digoxin in the blood may decrease with the concurrent administration of the following medications:

• Antacids.
• Some laxatives.
• Caolín-pectin (antidiarrheal medication).
• Neomycin, penicillamine, rifampicin (antibiotics).
• Some cytostatics (cancer medications).
• Metoclopramide (medication for the treatment of vomiting).
• Sulfasalazine (anti-inflammatory medication for the stomach).
• Adrenaline (a hormone).
• Salbutamol (medication for the treatment of asthma).
• Colestiramine (medication for the treatment of cholesterol).
• Fenitoína (medication for the treatment of epilepsy).

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant or plan to become pregnant, consult your doctor or pharmacist before using this medication.

As with all medications, the use of only digoxin during pregnancy should be considered when the expected clinical benefit of treatment for the mother outweighs any possible risk to the fetus.

Although digoxin passes into breast milk, the amounts are minimal.

Driving and operating machinery

No data are available on how digoxin affects driving or operating machinery, so be careful not to perform tasks that require special attention until you check how you tolerate the medication.

Digoxina Kern Pharma contains lactose

This medication contains lactose. If your doctor has told you that you have an intolerance to certain sugars, consult with him before taking this medication.

Follow exactly the administration instructions of this medication as indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

The digoxin dose for each patient must be established individually according to age, net body weight, and renal function. The suggested doses only aim to serve as an initial guide.

Your doctor must take into account the difference in effects between the administration of digoxin in oral and injectable forms when switching from one pharmaceutical form to another. For example, if a patient is switched from oral to intravenous formulation, the dose should be reduced by at least 33%.

The normal dose is:

Adults and children over 10 years:

Initial dose (loading dose):

• Fast oral administration:

750 to 1500 micrograms (0.75 to 1.5 mg) as a single dose.

• Slow oral administration:

250 to 750 micrograms (0.25 to 0.75 mg) should be administered daily for 1 week.

Maintenance dose:

Your doctor will indicate your maintenance dose, depending on your response to the initial treatment with this medication.

On average, most patients will be maintained on 125 to 750 micrograms (0.125 to 0.75 mg) of digoxin per day. However, in those who show greater sensitivity to digoxin adverse reactions, a dose of 62.5 micrograms (0.0625 mg) per day or less may be sufficient.

Newborns, infants, and children under 10 years (if they have not received cardiac glycosides in the preceding 2 weeks):

Initial oral dose:

Doses in children depend on their weight.

However, these doses range from 25 to 45 micrograms over 24 hours.

The initial dose should be administered in divided doses, with approximately half of the total dose given as the first dose and additional fractions of the total dose administered at intervals of 4 to 8 hours, with clinical response evaluated before each additional dose.

Maintenance dose:

Your doctor will indicate the maintenance dose, depending on the child's response to the initial treatment with this medication.

On average, most patients will be maintained on 20% to 25% of the initial dose, administered every 24 hours.

If you take more Digoxina Kern Pharma than you should:

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicological Information Service, phone: 91 562 04 20, indicating the medication and the amount ingested.

If you forgot to take Digoxina Kern Pharma:

Do not take a double dose to compensate for the missed doses.

If you have any other questions about the use of this product, ask your doctor or pharmacist.

Like all medications, digoxin can cause side effects, although not everyone will experience them.

Digoxin side effects generally depend on the dose and occur at higher doses than those required to achieve a therapeutic effect. Consequently, side effects are less common when digoxin is used within the recommended dose range or within the therapeutic concentration range in serum and careful attention is paid to the conditions and medications administered concurrently.

Cardiac disorders:

Cardiac arrhythmias and alterations in heart conduction, including:

• Pre-excitation of ventricular contractions that may evolve into bigeminism (a cardiac rhythm alteration in which normal heartbeats alternate with premature beats) or even trigeminism (a cardiac rhythm alteration in which two normal heartbeats alternate with a premature beat).
• Atrial tachycardias (cardiac rhythm disorder, such as rapid heartbeats originating in the upper chambers of the heart). They are often accompanied by atrioventricular block (conduction disorder between the upper and lower chambers of the heart) and not always is the pulse rapid (see section 2).
• Alterations in the electrocardiogram result.
• Bradycardia (a disorder that produces a decrease in the heart rate). Especially in children, it may be a sign of digoxin intoxication.
• In children, digoxin use can cause any type of arrhythmia. The most common are conduction alterations or supraventricular tachyarrhythmias (cardiac rhythm alterations not originating in the ventricles).

Gastrointestinal disorders:

Anorexia, nausea, and vomiting that disappear a few hours after ingesting the medication.

Diarrea may also occur.

Oral digoxin has also been associated with intestinal ischemia (interruption of blood supply to the intestine) and, rarely, with intestinal necrosis (death of part of the intestine due to interruption of blood supply).

Reproductive system and breast disorders:

Gynecomastia (breast development in a man) may occur with long-term administration.

Nervous system disorders:

Weakness, apathy, fatigue, discomfort, headache, visual disturbances, depression, and even psychosis have been reported.

Skin and subcutaneous tissue disorders:

Urticarial (hives) or scarlatiform (generalized redness of the skin with small raised lesions) skin eruptions.

Blood and lymphatic system disorders:

Pronounced eosinophilia (increase in the number of white blood cells in the blood).

Thrombocytopenia (decrease in the number of platelets in the blood).

If you experience side effects, consult your doctor or pharmacist, even if they are not listed in this prospectus.

Keep this medication out of the sight and reach of children.

No special storage conditions are required.

Do not use this medication after the expiration date that appears on the packaging after “CAD”. The expiration date is the last day of the month indicated.

Medications should not be disposed of through drains or in the trash. Dispose of packaging and unused medications at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of packaging and unused medications. By doing so, you will help protect the environment.

Digoxin Kern Pharma Composition

• The active ingredient is digoxin.
• The other components are: lactose, rice starch, hydrolyzed cornstarch, and magnesium stearate.

Appearance of the product and contents of the package

Rounded, biconvex tablets, white in color, with a groove on both sides. The groove serves to break and facilitate swallowing, but not to divide the tablet into equal doses.

Containers containing 50 tablets or 500 tablets.

Other presentations

• Digoxin Kern Pharma 0.25 mg/ml injectable solution. Each container contains 5 ampoules of 2 ml.
• Digoxin 0.05 mg/ml pediatric oral solution marketed under the name Lanacordin Pediatric. Container of 60 ml provided with a dosing syringe.

Holder of the marketing authorization and responsible for manufacturing

Kern Pharma, S.L.

Pol. Ind. Colón II, C/Venus, 72

08228 Terrassa (Barcelona)

Spain

Last review date of this leaflet: June 1998

The detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

___________________________________________________________________________

This information is intended only for doctors or healthcare professionals:

The greatest therapeutic benefit of digoxin is obtained in patients with ventricular dilation.

MODE OF ADMINISTRATION:

The intramuscular route is painful and associated with muscle necrosis (death of cardiac muscle cells). This route cannot be recommended.

Fast intravenous injection can cause vasoconstriction, leading to hypertension and/or reduced coronary flow. Therefore, a slow injection rate is important in heart failure with hypertension and acute myocardial infarction.

Adults and children over 10 years:

Initial dose (loading dose):

• Fast oral administration:

750 to 1500 micrograms (0.75 to 1.5 mg) as a single dose.

In less urgent cases, or when there is a higher risk of toxicity, for example in the elderly, the loading dose by oral administration should be administered in divided doses every 6 hours, administering approximately half of the total dose in the first dose. The clinical response should be evaluated before administering each additional dose (see section 2).

• Slow oral administration:

250 to 750 micrograms (0.25 to 0.75 mg) should be administered daily for 1 week, followed by an adequate maintenance dose. Clinical response should be observed within a week.

NOTE: The choice between a slow or fast oral digitalization protocol will depend on the patient's clinical condition and the urgency of the clinical indication.

Maintenance dose:

Your doctor will indicate your maintenance dose, depending on your response to initial treatment with this medication.

On average, most patients will be maintained on 125 to 750 micrograms (0.125 to 0.75 mg) of digoxin per day. However, in those who show greater sensitivity to digoxin adverse reactions, a dose of 62.5 micrograms (0.0625 mg) per day or less may be sufficient.

The maintenance dose should be based on the percentage of body reserves lost daily by elimination. The following formula has had extensive clinical use:

Maintenance dose = Maximum body reserves xdaily loss (percentage)

100

Where:

• Maximum body reserves = loading dose

Daily loss (percentage) = 14 + creatinine clearance (Ccr) / 5

• Ccr is creatinine clearance corrected for a body weight of 70 kg or 1.73 m2of body surface area. If only serum creatinine concentrations are available, an estimated Ccr (corrected for a body weight of 70 kg) in men is:

Ccr =(140 - age)

Scr (in mg/100 ml)

NOTE: When serum creatinine values are obtained in micromol/L, these can be converted to mg/100 ml (mg%) as indicated below:

Scr (mg/100 ml) = Scr (micromol/L) x 113.12

10,000

= Scr (micromol/L)

88.4

• Where 113.12 is the molecular weight of creatinine.
• In women, this result should be multiplied by 0.85.
• These formulas cannot be used for creatinine clearance in children.

In practice, this means that most patients will be maintained on 125 to 750 micrograms (0.125 to 0.75 mg) of digoxin per day. However, in those who show greater sensitivity to digoxin adverse reactions, a dose of 62.5 micrograms (0.0625 mg) per day or less may be sufficient.

Newborns, infants, and children under 10 years (unless they have received cardiac glycosides in the past 2 weeks):

Initial dose by oral administration:

Doses in children depend on their weight.

However, these doses range from 25 to 45 micrograms per 24 hours.

The initial dose should be administered in divided doses, administering approximately half of the total dose as the first dose and additional fractions of the total dose at intervals of 4 to 8 hours, evaluating the clinical response before administering each additional dose.

Maintenance:

Your doctor will indicate your maintenance dose, depending on your response to initial treatment with this medication.

On average, most patients will be maintained on 20% to 25% of the initial dose, administered every 24 hours.

In newborns, especially premature infants, digoxin renal clearance is reduced, and appropriate dose reductions should be considered, above general dosing instructions.

After the newborn phase, children generally require doses proportionally larger than adults based on weight or body surface area, as indicated in the following table. Children over 10 years require adult doses proportional to their body weight.

• Initial dose by oral administration:

This should be administered according to the following program:

Newborns premature <1.5 kg25 micrograms/kg per 24 hours.

Newborns premature 1.5 kg - 2.5 kg30 micrograms/kg per 24 hours.

Newborns at term to 2 years45 micrograms/kg per 24 hours.

2 to 5 years35 micrograms/kg per 24 hours.

5 to 10 years25 micrograms/kg per 24 hours.

The initial dose should be administered in divided doses, administering approximately half of the total dose as the first dose and additional fractions of the total dose at intervals of 4 to 8 hours, evaluating the clinical response before administering each additional dose.

• Maintenance:

The maintenance dose should be administered according to the following program:

Newborns premature:

Newborns at term and children up to 10 years:

These dosing schemes are designed to be a guideline, and careful clinical observation and control of digoxin serum levels (see Control) should be performed to adjust the dose in these pediatric patient groups.

If cardiac glycosides have been administered in the past 2 weeks, the optimal loading doses of digoxin will be lower than those recommended above.

Cardiac glycosides are an important cause of accidental poisoning in children. The tolerance of newborns to cardiac glycosides is variable, as renal clearance of the medication is reduced. Premature and immature newborns are especially sensitive.

Older adults:

The tendency to alter renal function and the low net body mass in older adults affects the pharmacokinetics of this medication, making it easy to develop elevated serum digoxin levels and associated toxicity, unless lower doses of digoxin are used than those used in non-elderly patients. Serum digoxin levels should be regularly monitored, and hypokalemia should be avoided.

Recommendations for Dosage in Specific Patient Groups:

See "Warnings and Precautions" section.

Control:

Digoxin serum concentrations can be expressed in conventional units of ng/ml or in SI units of nmol/L. To convert ng/ml to nmol/L, multiply ng/ml by 1.28.

Digoxin serum concentration can be determined by radioimmunoassay. Blood should be drawn every 6 hours or more after the last dose of this medication. There are no strict guidelines on the interval of serum concentrations that are most effective, but most patients will benefit, with little risk of developing signs and symptoms of toxicity, with digoxin concentrations between 0.8 ng/ml (1.02 nmol/L) and 2.0 ng/ml (2.56 nmol/L). Above this interval, signs and symptoms of toxicity may be more frequent, and levels above 3.0 ng/ml (3.84 nmol/L) are likely to be toxic. However, to decide whether a patient's symptoms are due to digoxin, the clinical condition, serum potassium levels, and thyroid function are important factors to consider.

Other glycosides, including digoxin metabolites, may interfere with available assays, so caution should be exercised when values do not appear to be consistent with the patient's clinical condition.

SYMPTOMS OF OVERDOSE AND TREATMENT:

Adults:

In adults without heart disease, clinical observation indicates that a digoxin overdose of 10-15 mg was the dose that led to death in half of the patients. If an adult without heart disease ingested more than 25 mg of digoxin, death or progressive toxicity would occur, responding only to the administration of specific fragments of antibodies that bind to digoxin.

Children:

In children aged 1 to 3 years without heart disease, clinical observation suggests that a digoxin overdose of 6 to 10 mg was the dose that led to death in half of the patients. If more than 10 mg of digoxin were ingested by a child aged 1 to 3 years without heart disease, the outcome would be invariably fatal if fragments of antibodies were not administered.

After recent ingestion, either accidentally or intentionally, the available load for absorption could be reduced by gastric lavage.

Patients who have ingested a large amount of digital should receive large doses of activated charcoal to prevent absorption and to bind to digoxin in the intestine during enterohepatic recirculation.

If hypokalemia exists, it should be corrected with potassium supplements, either orally or intravenously, depending on the urgency of the situation. In cases where a large amount of digoxin has been ingested, hyperkalemia may occur due to the release of potassium from skeletal muscle. Before administering potassium in cases of digoxin overdose, serum potassium levels should be known.

Bradycardias may respond to atropine, but temporary pacing may be required. Ventricular arrhythmias may respond to lignocaine (anesthetic medication) or phenytoin (epilepsy medication).

Dialysis is not particularly effective for eliminating digoxin from the body in cases of life-threatening toxicity.

After intravenous administration of specific fragments of antibodies against digoxin (of ovine origin), rapid reversal of complications associated with severe digoxin poisoning, digitoxin, and related glycosides occurs.