MEGAMILBEDOCE 5,000 micrograms/mL Injectable Solution

2. What you need to know before you use Megamilbedoce

Do not use Megamilbedoce:

• if you are allergic to the active substance, to cobalamins (vitamin B12, other forms), to cobalt or to any of the other components of this medicine (listed in section 6).

Warnings and precautions

Consult your doctor before starting to use Megamilbedoce.

• In case of anemia, the vitamin B12 deficit must be confirmed before starting treatment, so it is very likely that your doctor will indicate that you undergo blood and urine tests. During treatment, you will also be asked to undergo periodic tests to control your blood cells and vitamin B12 and other product levels.
• Before injectable treatment, your potassium levels in the blood must be monitored, and if necessary, this product must be administered to avoid the possibility of a severe reaction.

• Caution is required in parenteral administration (intramuscular or intravenous), as some sensitive patients may experience anaphylactic shock (generalized allergic reaction) and angioedema (rapid swelling of the skin, mucous membranes, and surrounding tissues). For this reason, it is recommended to administer a test dose to patients who may be sensitive.
  • If you have a predisposition to gout, you should be cautious because hydroxocobalamin can precipitate a gout crisis.
  • The effect of treatment with vitamin B12 (the active substance of this medicine) decreases in situations such as uremia (increase in nitrogenous substances in the blood), infections, iron or folic acid deficiency, and with the administration of bone marrow suppressant medications (e.g., chloramphenicol).
  • This medicine may mask the symptoms of polycythemia vera (a blood disease).
  • In the case of intravenous administration (directly into a vein), a rise in blood pressure may occur.
  • The administration of large amounts of hydroxocobalamin intravenously in a parenteral nutrition solution would result in almost total loss through urine (see the last section of the leaflet).

Interference with analytical tests: If you are going to undergo any diagnostic test (including blood tests, urine tests, skin tests that use allergens, etc.), inform your doctor that you are taking this medicine, as it may alter the results.

Children and adolescents

Although this medicine should not be used in children under 3 years of age whenever possible (see section Megamilbedoce contains benzyl alcohol and sodium), it may be used in this population if considered essential, administered under medical supervision.

Use of Megamilbedoce with other medicines

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

Megamilbedoce may interact with the following medicines:

• Chloramphenicol (antibiotic).
• Oral contraceptives.
• Several medications can interfere with hydroxocobalamin (vitamin B12) and may decrease its absorption if taken orally, including: aminoglycoside antibiotics such as neomycin, colchicine (medicine for gout), mesalazine (for intestinal diseases), medications for ulcers (cimetidine, ranitidine, etc.), medications for epilepsy (phenytoin, phenobarbital, primidone, etc.), sustained-release potassium preparations, cobalt radiation, ascorbic acid supplements, and excessive alcohol consumption.

Use of Megamilbedoce with alcohol

Excessive alcohol consumption decreases the absorption of vitamin B12.

Pregnancy, breastfeeding, and fertility

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

Currently, there are no well-controlled studies in pregnant women.

The use of Megamilbedoce is not recommended during pregnancy.

Vitamin B12 is excreted in breast milk. Given the lack of safety information, the use of Megamilbedoce is contraindicated during breastfeeding.

Driving and using machines

The influence of Megamilbedoce on the ability to drive and use machines is insignificant. However, this medicine may cause dizziness in some patients, who should not drive or use hazardous machines.

Megamilbedoce contains benzyl alcohol and sodium

This medicine should not be administered to premature or newborn infants because it contains 4 mg of benzyl alcohol per ampoule. It can cause toxic reactions and allergic reactions in children under 3 years of age.

(See section Children and adolescentsin section 2.)

This medicine contains less than 23 mg (1 mmol) of sodium per ampoule, so it is considered essentially "sodium-free".

3. How to use Megamilbedoce

Follow the administration instructions of this medicine exactly as indicated by your doctor. If in doubt, consult your doctor again.

The recommended doses are:

The doses vary according to the indications.

Intramuscular routeor, in the case of gastrectomized patients (with complete or partial stomach removal), by intramuscular or deep subcutaneous route.

Adults

• Vitamin B12 deficiency in uncomplicated pernicious anemia or malabsorption of vitamin B12:

The recommended initial dose is 100 micrograms of hydroxocobalamin (0.02 ml of solution) per day, for 5-10 days, followed by 100-200 micrograms (0.02-0.04 ml of solution) per month, until improvement. After remission, a maintenance dose of 100 micrograms per month is recommended.

An alternative treatment regimen with higher doses may be necessary: between 250 and 1,000 micrograms (0.05-0.2 ml of solution) intramuscularly on alternate days, for 1 or 2 weeks, followed by 250 micrograms (0.05 ml) per week, until remission; maintenance dose of 1,000 micrograms every 2 or 3 months.

• Complicated pernicious anemia or malabsorption of vitamin B12 with neurological complications (in the nervous system): the most common administration regimen is 1,000 micrograms of hydroxocobalamin (0.2 ml of injectable solution) per day during the first week of treatment, continuing with a dose of 1,000 micrograms (0.2 ml) per week for a month, and then 1,000 micrograms (0.2 ml) per month as a maintenance dose until the cause is cured.

Patients with pernicious anemia or vitamin B12 deficiency due to another irreversible cause require lifelong maintenance treatment.

• Prophylaxis of anemia in gastrectomized patients: 1,000 micrograms (0.2 ml) every 2 or 3 months, by intramuscular or deep subcutaneous route.
• Dietary vitamin B12 deficiency, such as in strict vegetarians: a dose of 100 micrograms (0.02 ml) per month can be administered by intramuscular route, with periodic blood tests.
• Metabolic disorders:
  • Methylmalonic acidemia with homocystinuria: The minimum dose to be administered is 1,000 micrograms (0.2 ml) per day by intramuscular route, which can be replaced by the administration of 1,000 micrograms (0.2 ml) by intramuscular route on alternate days. If necessary, these doses can be doubled (up to 2,000 micrograms per administration, i.e., 0.4 ml of Megamilbedoce).
  • Methylmalonic acidemia without homocystinuria: Some of these improve with hydroxocobalamin, at a dose of 1,000 micrograms (0.2 ml) per week, by intramuscular route. If no improvement is observed, your doctor will suspend treatment.

Use in children

Although Megamilbedoce should not be used in children under 3 years of age whenever possible due to its content of benzyl alcohol (see Megamilbedoce contains benzyl alcohol and sodiumin section 2), it may be used if the doctor considers it essential, administered under their supervision.

The requirements vary with age.

• In children with uncomplicated pernicious anemia or malabsorption of vitamin B12, the recommended dose is 30 to 50 micrograms per day (between 0.006 and 0.01 ml), for 2 or more weeks, until a total dose of 1,000 to 5,000 micrograms of hydroxocobalamin (between 0.2 and 1 ml); a maintenance dose of 100 micrograms per month (0.02 ml) will be followed.
• In pernicious anemia or vitamin B12 deficiency due to another irreversible cause, the recommended dose is 1,000 micrograms (0.2 ml) intramuscularly every 2 or 3 days, until a total of 5 doses; the maintenance dose is 1,000 micrograms every 3 months.
• Metabolic disorders:
  • Methylmalonic acidemia with homocystinuria: The minimum dose to be administered is 1,000 micrograms (0.2 ml) per day by intramuscular route, which can be replaced by the administration of 1,000 micrograms (0.2 ml) by intramuscular route on alternate days. If necessary, these doses can be doubled (up to 2,000 micrograms per administration, i.e., 0.4 ml of Megamilbedoce). In smaller children, a dose of 200 micrograms/kg of body weight (0.04 ml/kg) per day is proposed.
  • Methylmalonic acidemia without homocystinuria: Some of these improve with hydroxocobalamin, at a dose of 1,000 micrograms (0.2 ml) per week, by intramuscular route. If no improvement is observed, your doctor will suspend treatment.

In other enzymatic deficiencies of vitamin B12 metabolism, patients can be treated with similar doses to those mentioned above, depending on the response.

In metabolic disorders, if oral administration is to be used, a dose of 10,000 micrograms (1 ampoule) is recommended for both adults and children, but due to poor absorption by this route, vitamin B12 levels should be checked with tests one week after administration.

In methylmalonic acidemia with homocystinuria, this route of administration should not be used, as adequate hydroxocobalamin levels are not achieved.

Method of administration:

(See also the last section of the leaflet.)

Megamilbedoce is administered primarily by intramuscular routeand in the case of gastrectomized patients (with complete or partial stomach removal) by intramuscular routeor by deep subcutaneous route.

It may also be possible, in certain cases, to administer it by the following routes:

• Oral route: it can be administered orally in patients who do not tolerate the intramuscular route, as long as they do not have serious digestive tract disorders that affect absorption. The absorption of hydroxocobalamin by the oral route is irregular, so tests should be performed to check.

If administered orally, it can be taken directly or dissolved in liquid.

• Intravenous route: hydroxocobalamin could be administered intravenously in very specific cases and only when indicated by a doctor, as it presents a risk of anaphylactic reactions (exaggerated allergic reactions). It will be administered by direct intravenous infusion.

If you use more Megamilbedoce than you should

Even in accidental overdoses, no cases of intoxication are known. In rare cases, a severe allergic reaction may occur.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or go to a medical center or call the Toxicology Information Service, Telephone 91 562 04 20, indicating the medicine and the amount ingested.

If you forget to use Megamilbedoce

Do not use a double dose to make up for forgotten doses.

If you forget to administer your corresponding dose, administer it as soon as possible.

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

4. Possible side effects

Like all medicines, Megamilbedoce can cause side effects, although not everyone gets them.

These are generally infrequent but moderately important.

The assessment of side effects is based on the following frequencies:

The following side effects may occur; the frequency of some of them is not known with certainty:

• Frequently, reduction of lymphocyte count (a type of white blood cell).
• Possible masking of polycythemia (a blood disease).
• Infrequently, pain at the injection site.
• Allergic reactions, with chest tightness, angioedema (rapid swelling of the skin, mucous membranes, and surrounding tissues), urticaria (red-roded hives accompanied by burning or itching), itching, difficulty breathing; frequently, skin redness, eruptions (especially acne-like); photosensitivity (sensitivity to sunlight).
• Rarely, anaphylactic reaction (generalized allergic reaction).
• Decrease in potassium levels in the blood after administration of the medicine.
• Very frequently, headache.
• Restlessness, dizziness, swelling, irritation, and redness of the eyes.
• Rarely, arrhythmias (irregular heartbeats).
• It is possible to have congestive heart failure at the beginning of treatment.
• Hot flashes, peripheral edema (swelling of ankles, feet, and legs); peripheral vascular thrombosis (formation of a clot that obstructs circulation in a blood vessel outside the heart, usually in the legs or feet).
• With intravenous administration, hypervolemia (increase in total blood volume) and

very frequently, increased blood pressure; frequently, reaction at the injection site.

• Difficulty breathing or "suffocation syndrome" in premature infants, due to the content of benzyl alcohol (see sections Megamilbedoce contains benzyl alcohol and sodiumin section 2 and Use in childrenin section 3). Rarely, pulmonary edema (infiltration of fluid in the lungs).
• Frequently, nausea.
• Digestive disorders, transient diarrhea.
• Very frequently, reddish discoloration of the urine.

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

5. Storage of Megamilbedoce

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

Do not use this medicine 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 wastewater or household waste. Deposit the packaging and medicines you no longer need at the SIGRE collection point in the pharmacy. If in doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Container contents and additional information

Composition ofMegamilbedoce 10,000 micrograms Injectable Solution

• The active ingredient is hydroxocobalamin (vitamin B12).

A 2 ml ampoule contains 10,000 micrograms of hydroxocobalamin.

1 ml of solution contains 5,000 micrograms of hydroxocobalamin.

• The other components (excipients) are: benzyl alcohol (4 mg per ampoule), sodium chloride, and water for injectable preparations.

Appearance of the product and container contents

The medication is a solution presented in topaz-colored ampoules containing a clear red liquid.

Box of 10 ampoules of 2 ml.

Marketing authorization holder

Aristo Pharma Iberia, S.L.

C/ Solana, 26

28850, Torrejón de Ardoz

Madrid, Spain

Manufacturer

LABORATORIOS MEDICAMENTOS INTERNACIONALES, S.A. (MEDINSA)

C/ Solana, 26

28850 – Torrejón de Ardoz (Madrid)

Date of the last revision of this prospectus:November 2012

Other sources of information

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended solely for doctors or healthcare professionals:

Intramuscular injection will be performed in a large muscle mass.

Intravenous administration will be performed by including small amounts of hydroxocobalamin in a parenteral nutrition solution.