Package Insert: Information for the User

Lanirapid 0.1 mg Tablets

β-Metildigoxina

Read this package insert carefully before taking this medicine, as it contains important information for you.

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

Lanirapid belongs to a group of medications known as cardiac glycosides (digitals). Its active ingredient is β-Metildigoxina, which acts on heart cells by increasing the force and speed of contraction, delaying the conduction of the stimulus and increasing the ventricular response to the stimulus.

This medication is indicated for the treatment of:

• Congestive heart failure (when the heart does not pump enough blood and fluid accumulates in the lungs).
• Cardiac rhythm disturbances (heart rhythm): atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (problems with heart rate and rhythm).

Do not take Lanirapid

• if you are allergic to β-Metildigoxina or any of the other components of this medication (listed in section 6);
• if you have carotid sinus syndrome (sudden episodes of dizziness and loss of consciousness) and thoracic aortic aneurysm (dilation of the aorta at the level of the chest);
• if you have hypertrophic obstructive cardiomyopathy (a type of heart alteration);
• if you have Wolff-Parkinson-White syndrome (a type of heart disease) or any other evidence of an accessory pathway;
• if you have tachycardia (rapid or irregular heart rhythm) or ventricular fibrillation (very abnormal heart rhythm that can be fatal).

Warnings and precautions

Consult your doctor or pharmacist before starting to take this medication in any of the following cases:

• If you have taken another digitalis medication in the 2 weeks prior to using this medication, as your doctor will consider reducing the initial dose.
• If you have hypokalemia (low potassium levels in the blood), as it may increase the effect of this medication. You should be aware of the need to monitor potassium levels in the blood, especially when using diuretics at the same time.
• If you have hypomagnesemia (low magnesium levels in the blood), as it may increase the effect of this medication, and it may be necessary to reduce the dose.
• If you have hypercalcemia (high calcium levels in the blood), as it may increase the effect of this medication, and it may be necessary to reduce the dose.
• If you have hypoxia (lack of oxygen in the body's tissues), as it may increase the effect of this medication, and it may be necessary to reduce the dose.
• If you have problems with thyroid function: In the case of hypothyroidism (decreased production of hormones in the thyroid gland), the effect of this medication may be increased, and it may be necessary to reduce the dose. On the other hand, in the case of hyperthyroidism (increased production of hormones in the thyroid gland), higher doses than usual may be required. In these patients, it will also be taken into account that any change in the state of thyroid function may affect the response to the established dose (see section 3).
• If you have recently had a myocardial infarction (heart attack), have advanced respiratory insufficiency (decreased respiratory function) or rheumatic carditis (inflammation of the heart), as it usually increases sensitivity to digitalis. In these cases, the dose will be adjusted with due caution.
• If you have kidney failure, as it may cause accumulation of the medication, and the dose should be adjusted according to the degree of failure (see section 3).
• If you take natural products or plant extracts that contain Hypericum perforatum, as it may decrease the effect of this medication.

It is essential to note that the heart rhythm disturbances caused by an increase in digitalis dose are very similar to certain clinical conditions where digitalis is indicated. The medication will be used with maximum caution in cases where it cannot be completely ruled out that the condition being treated has a cause that is a digitalis intoxication.

Furthermore, special caution should be exercised in cases of alterations in the formation or conduction of the stimulus with bradycardia, as well as before cardioversion. It will be used only if absolutely necessary and with maximum caution in cases of complete conduction block (AV block of degrees II and III), Adams-Stokes syndrome, aortic stenosis, or glomerular kidney disease (glomerulonephritis).

Children and adolescents

The sensitivity to β-Metildigoxina may increase in the pediatric population (children and adolescents).

Taking Lanirapid with other medications

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

The combination of this medication with other medications may cause an increase or decrease in the effects of β-Metildigoxina.

The medications that may increase the action of β-Metildigoxina are:

• Calcium
• Diuretics and laxatives
• Penicillins (antibiotic medications)
• Anfotericina B (medication that prevents the growth of certain fungi)
• Carbenoloxona (medication used to relieve ulcers)
• Glucocorticoids (medications)
• ACTH (a type of hormone)
• Salicylates (medications that relieve pain and reduce fever)
• Verapamilo, dilitiazem, and captopril (medications used to treat hypertension)
• Antiarrhythmic medications, such as quinidina, amiodarona, procainamida, and propafenona
• Tetraciclinas and eritromicina (antibiotic medications)
• Reserpina and Rauwolfia alkaloids (medications used to treat hypertension)
• Beta-blockers (medications for the heart)
• Chloruro de suxametonio, pancuronio, succinilcolina (muscle relaxants)
• Tricyclic antidepressants (medications for depression)
• Sympathomimetic substances (such as efedrina and adrenergic agents)
• Theophylline (medication to facilitate breathing)
• Epinefrina (heart stimulant)
• Thyroid medications

The medications that may decrease the action of β-Metildigoxina are:

• Potassium ions
• Antidiarrheal medications of the type of intestinal absorbents (such as activated charcoal or pectin)
• Ionic exchange resins (such as colestiramina, colestipol)
• Antacids
• Neomicina, ácido paraaminosalicílico (antibiotic medications)
• Cytostatics (medications used to treat cancer)
• Fenitoína (medication used to treat epilepsy).

Special attention should be paid if this medication is combined with medications that increase heart function or with medications that induce hypokalemia and hypomagnesemia.

Pregnancy, lactation, and fertility

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

Pregnancy:

Your doctor will decide if you can take this medication during pregnancy, as it should be used only if the expected benefit for the mother outweighs the possible risk to the fetus.

Lactation:

β-Metildigoxina is eliminated in breast milk.

This medication should be used only when strictly necessary, under medical control, and the heart rate of the infants should be monitored.

Driving and operating machinery

No data are available on how β-Metildigoxina affects driving or operating machinery, so avoid performing tasks that require special attention until you check how you tolerate the medication.

Lanirapid 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. In case of doubt, consult your doctor or pharmacist again.

Both the initial dose and the maintenance dose must be established individually for each patient, in accordance with the plasma concentration.

The dose depends on the needs of cardiac glycosides and the rate of elimination. The amount needed will change if you suffer from problems with the thyroid gland function, have kidney failure or are an elderly person (see section “Use in special populations”).

As a maintenance dose, most patients need 2 to 3 tablets a day (that is, between 0.2 and 0.3 mg of β-metildigoxina per day). In isolated cases, one tablet a day (0.1 mg of β-metildigoxina per day) is sufficient. Only in patients with high needs for glycoside, a daily maintenance dose of 0.4 mg of β-metildigoxina (4 tablets a day) is indicated.

The following table may serve as a guide for both initial treatment and maintenance treatment with doses of 2 and 3 tablets a day (that is, 0.2 and 0.3 mg of β-metildigoxina per day):

In cases of severe heart failure (severe heart failure) and according to your glycoside needs, your doctor may consider a faster start treatment. For example, an administration of 0.6 mg of β-metildigoxina per day (that is, 2 tablets of Lanirapid three times a day) for 2 to 4 days, would be equivalent to a maintenance dose of 2 to 4 tablets a day.

Administration form

The tablets should be swallowed without chewing, preferably after meals and with a little liquid.

The tablet can be divided into equal doses.

Use in special populations

Patients with kidney failure:

In patients with renal insufficiency, the dose of metildigoxina must be adjusted according to the creatinine clearance.

Patients of advanced age:

In elderly patients, the dose of metildigoxina must be adapted according to renal function. The decrease in renal function in this group of patients must be determined by calculating the creatinine clearance.

Patients with thyroid function disorders:

In patients with hypothyroidism, it may be necessary to reduce the dose of metildigoxina. On the other hand, patients with hyperthyroidism may need higher doses of metildigoxina, depending on the serum concentration of thyroid hormones.

Use in children and adolescents

There is no specific recommendation for the use of this medication in pediatric population. There are no data on the dose in pediatric population, so it is not recommended for use in this population.

If you take more Lanirapid 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 Lanirapid

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

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

The majority of side effects attributed to digitalis are manifestations ofoverdose.

Blood and lymphatic system disorders

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

Immune system disorders (system responsible for the body's defense)

Immunological reactions (such as lupus erythematosus) and eosinophilia.

Metabolism and nutrition disorders

Anorexia

Nervous system disorders

Alterations in the central nervous system (such as headaches, facial pain, dizziness, fatigue, drowsiness, insomnia, mental changes, disorientation, depression, apathy, hallucinations, delirium, and acute psychosis).

Eye disorders

Visual disturbances (colored vision or halos, yellow vision, blurred vision, decreased visual acuity, or double vision).

Cardiac disorders

Bradycardia and arrhythmias, tachycardia, and AV block of degree II and III.

In the case of β-metildigoxina overdose, cardiac arrhythmias (alterations in heart rhythm) can increase to the point of producing life-threatening alterations in heart rhythm in the case of severe poisoning.

Gastrointestinal disorders

Increased salivation, loss of appetite, diarrhea, nausea, vomiting, abdominal pain, mesenteric infarction.

Skin and subcutaneous tissue disorders (tissue under theskin)

Allergic reactions (such as erythema).

Musculoskeletal and connective tissue disorders (group of diverse tissues)

Muscle weakness.

Reproductive and breast disorders

Gynecomastia (enlargement of male breasts).

Other adverse effects in children and adolescents

Cardiac arrhythmias are usually the first sign of overdose in children, and are fundamentally nodal or auricular in nature.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is an adverse effect that does not appear in this leaflet. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for human use:www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

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.

Medicines 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 unused packaging and medications. By doing so, you will help protect the environment.

Composition of Lanirapid

• The active principle is β-Metildigoxina. Each tablet contains 0.1 mg of β-Metildigoxina.
• The other components are lactose, microcrystalline cellulose (E-460(i)), sodium carboxymethyl starch, colloidal anhydrous silica, magnesium stearate, and povidone.

Appearance of the product and contents of the package

White, round, and scored tablet. The tablet can be divided into equal doses.

It is presented in standard containers of 50 tablets, conditioned in PVC/Aluminum blisters.

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: November 2013.

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

This information is intended only for doctors or healthcare professionals:

MODE OF ADMINISTRATION:

Posology and form of administration

The starting dose and maintenance dose must be established individually for each patient, monitoring plasma concentration.

The tablets of this medicine should be swallowed without chewing, preferably after meals and with a little liquid.

The dose depends on the needs of cardiac glycosides and the rate of elimination. The amount needed will vary in patients with renal insufficiency, elderly people, and patients with thyroid function disorders (see "Special populations").

As a maintenance dose, most patients need 2 to 3 tablets a day (this is, between 0.2 and 0.3 mg of β-metildigoxina per day). In isolated cases, one tablet a day (0.1 mg of β-metildigoxina per day) is sufficient. Only in patients with high needs for glycoside, a daily maintenance dose of 0.4 mg of β-metildigoxina (4 tablets a day) is indicated.

The following table may serve as a guide for a semirapid start treatment and for the maintenance therapy with doses of 0.2 and 0.3 mg of β-metildigoxina per day.

In severe cases of heart failure, and according to the individual's glycoside needs, a faster start treatment may be performed. For example, if it were determined that a certain person needs 0.6 mg of β-metildigoxina per day (2 tablets of Lanirapid three times a day) for 2 to 4 days, the level of effect thus reached would correspond to a daily maintenance dose of 0.2-0.4 mg of β-metildigoxina.

Pediatric population

There is no specific recommendation for the use of this medicine in the pediatric population.

Special populations

Patients with renal insufficiency:

In patients with renal insufficiency, the dose of metildigoxina must be adjusted according to the creatinine clearance. As a guide:

Creatinine clearance can be calculated using the Cockcroft and Gault equation (only applicable to adults):

(140 – age [years] x weight [kg])

Males: Clcr [ml/min] = ———————————————

72 x Ccr [mg/dl]

CLcr= Clearance of creatinine

Ccr= Serum concentration of creatinine

Females: For women, the clearance of creatinine corresponds to 85% of the value obtained with this equation.

Older adults:

In older adults, the dose of metildigoxina must be adapted according to renal function. The decrease in renal function in this group of patients must be determined by calculating the clearance of creatinine.

Patients with thyroid function disorders:

The dose of metildigoxina must be adjusted according to the serum concentration of thyroid hormones. In patients with hypothyroidism, it may be necessary to reduce the dose of metildigoxina. On the other hand, patients with hyperthyroidism may need higher doses of metildigoxina.

SYMPTOMS OF OVERDOSE AND TREATMENT:

The therapeutic margin of digitalis glycosides is narrow.

Depending on cardiac sensitivity and glycoside needs, the therapeutic plasma concentration of glycosides with this medicine is around 1 ng/ml, while signs of glycoside intoxication may appear with values above 2 ng/ml.

Symptoms of intoxication

The clinical symptoms correspond to those of digitalis intoxication; there is no typical sequence in which these symptoms appear.

Cardiac symptoms (worsening of heart failure, ventricular or supraventricular arrhythmias, and conduction defects) and extracardiac symptoms (anorexia, hypersalivation, nausea, vomiting, diarrhea, abdominal pain, facial pain, headache, muscle weakness, dizziness, somnolence, disorientation, nightmares, apathy, depression, visual disturbances, and in very rare cases, delirium, acute psychosis, and hallucinations) may appear simultaneously or consecutively. Cardiac symptoms of glycoside intoxication are much more severe than extracardiac symptoms.

Fatal outcomes of digitalis intoxication are due to the cardiotoxic action of glycosides. Arrhythmias are especially important, such as polymorphic ventricular extrasystoles, ventricular flutter, ventricular fibrillation, and asystole. Beyond the dose of glycoside, the severity of symptoms of intoxication depends on the content of potassium in the extracellular and intracellular compartments.

Treatment of intoxication

If more than 4 hours have not passed since the ingestion of the tablets, immediate gastric lavage should be performed. Prior administration of atropine (0.5-1.0 mg subcutaneously) is highly recommended, especially in cases of bradycardic alterations. In all other cases, activated charcoal should be administered.

All treatment should be performed with ECG monitoring.

• Treatment of the cause, antidotes

A fragment of digoxin antibody has been developed for cases with a risk of death due to digitalis intoxication, in which severe cardiac rhythm alterations are present, or when alterations are expected that would pose a risk of death due to accidental ingestion or after a suicide attempt. The digitalis antidote is linked to digoxin, digoxin derivatives, and digitoxin in inactive complexes of antibody-glycoside, rapidly inducing the causal elimination of symptoms of intoxication.

Forced diuresis, hemodialysis, and peritoneal dialysis have a slight influence on the excretion of glycosides. These techniques are therefore inappropriate for the treatment of digitalis intoxication.

• Treatment of symptoms

Mild symptoms of toxicity are treated by temporarily suspending medication, and if necessary, adding a potassium supplement orally (4 to 6 g/day in several doses, for adults with normal renal function).

Severe cases may require the administration of potassium intravenously (infusion of 20 mEq/hour until a total of 40-100 mEq), for adults. In children, 0.5 mEq/kg/hour until a maximum of 2 mEq/kg), under ECG control, and should be avoided in cases of advanced or total atrioventricular block, due to the glycoside and not related to tachycardia. Potassium administration is contraindicated in evident conduction alterations.

For convenience, a differentiation is made in the symptomatic treatment between bradycardic and tachycardic rhythm alterations. However, it should always be taken into account that a change to causal treatment with fragments of antibodies should be considered at the opportune moment:

- In thebradycardic rhythm alterations(heart rate below 60 ppm): administration of atropine intravenously is recommended, 0.5 mg in adults and 0.02 mg/kg in children, repeated every 5 minutes and up to a maximum of 4 times. If this does not produce good results, it may be necessary to install a pacemaker (provisional).

• For thetreatment of tachycardias:
• • Supraventricular with signs of low output: Phenitoin (100 mg intravenously, repeatable every 5 minutes) may be used. In very specific cases in which the patient does not respond to phenitoin, esmolol (0.5 mg/kg intravenously in 1 minute, followed by continuous infusion of 0.05 mg/kg/min) may be tried. If there is no response to the above drugs and these rhythm disturbances have hemodynamic repercussions, recourse should be made to antibodies.
  • Ventricular arrhythmias: Phenitoin or lidocaine is recommended. Phenitoin intravenously in bolus of 50 mg per minute or 100 mg every 5 minutes, until the arrhythmia is controlled or a maximum of 1 g in adults or 20 mg/kg in children. Lidocaine would be used in bolus of 1.5 mg/kg intravenously followed by continuous infusion of 2.5-4 mg/min in adults and 50 micrograms/kg/min in children.

• In the case ofventricular tachycardias without pulse, the initial treatment of choice is defibrillation.

Other agents used in the treatment of digitalis intoxication include calcium ion sequestrants, quinidine, procainamide, or beta-blockers. These three should be used with caution in advanced cases of atrioventricular block.

Consideration should be given to the possibility of using cardioversion in cases where causal treatment cannot be administered at the opportune moment and if this symptomatic treatment does not produce good results.