Megamilbedoce 5,000 micrograms/ml solution for injection

Patient Information Leaflet

Introduction

Patient Information Leaflet

Megamilbedoce 10,000 micrograms Injectable Solution

Hydroxocobalamin

Read all of this leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only; do not pass it on to others, even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are effects not listed in this leaflet.

Leaflet Contents

1. What Megamilbedoce is and what it is used for
2. What you need to know before using Megamilbedoce
3. How to use Megamilbedoce
4. Possible adverse effects
5. How to store Megamilbedoce
6. Contents of the pack and other information

1. What Megamilbedoce is and what it is used for

Megamilbedoce contains a form of vitamin B12 in a very high dose, allowing for intensive administration with prolonged effect. Vitamin B12 plays a role in numerous metabolic processes in the body, including some related to the nervous system and the formation of blood cells.

Megamilbedoce is indicated for vitamin B12 deficiency states, such as:

• Pernicious anemia (a type of anemia), malabsorption syndromes (digestive absorption problems, as seen in intestinal inflammatory conditions such as sprue or Crohn's disease), gastrectomy (total or partial removal of the stomach), or significant ileal resection (removal of a large portion of a section of the small intestine). In strict vegetarians.
• Metabolic disorders: patients with methylmalonic acidemia (an inherited disorder in which a substance called methylmalonic acid accumulates in the blood), with or without homocystinuria.

2. What you need to know before using 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.

• If you have anemia, vitamin B12 deficiency must be confirmed before starting treatment; therefore, your doctor will likely recommend blood and urine tests. During treatment, periodic tests will also be required to monitor your blood cells, vitamin B12 levels, and other parameters.
• Before starting parenteral (injectable) treatment, your blood potassium levels should be monitored, and potassium supplementation may be necessary to prevent the occurrence of a serious reaction.
• Caution is required when administering parenterally (intramuscularly or intravenously), as in some sensitive patients, anaphylactic shock (generalized allergic reaction) and angioedema (rapid swelling of the skin, mucous membranes, and underlying tissues) may occur. For this reason, it is recommended to administer a test dose to patients who may be sensitive.
  • If you are predisposed to gout, exercise caution, as hydroxocobalamin may precipitate a gout attack.
  • The effect of vitamin B12 treatment (the active substance in this medicine) may be reduced in conditions such as uremia (elevated nitrogenous substances in blood), infections, iron or folic acid deficiency, and when using bone marrow suppressant drugs (e.g., chloramphenicol).
  • This medicine may mask the symptoms of polycythemia vera (a blood disorder).
  • Intravenous administration (directly into a vein) may cause an increase in blood pressure.
  • Administering large amounts of hydroxocobalamin intravenously as part of parenteral nutrition will result in almost complete excretion via urine (see the last section of the leaflet).

Interference with diagnostic tests: If you are scheduled for any diagnostic tests (including blood and urine tests, skin tests using allergens, etc.), inform your doctor that you are taking this medicine, as it may alter test 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, under strict medical supervision.

Using Megamilbedoce with other medicines

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines.

Megamilbedoce may interact with the following medicines:

• Chloramphenicol (an antibiotic).
• Oral contraceptives.
• Several medicines may interfere with hydroxocobalamin (vitamin B12) and reduce its absorption when taken orally, including: aminoglycoside antibiotics such as neomycin, colchicine (a medicine for gout), mesalazine (for intestinal diseases), ulcer medications (cimetidine, ranitidine, etc.), antiepileptic drugs (phenytoin, phenobarbital, primidone, etc.), sustained-release potassium preparations, cobalt radiation, ascorbic acid supplements, and excessive alcohol intake.

Using Megamilbedoce with alcohol

Excessive alcohol intake reduces vitamin B12 absorption.

Pregnancy, breastfeeding, and fertility

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

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

Megamilbedoce is not recommended during pregnancy.

Vitamin B12 is excreted in breast milk. Due to lack of safety data, the use of Megamilbedoce is contraindicated during breastfeeding.

Driving and using machines

The effect of Megamilbedoce on the ability to drive and operate machinery is negligible. However, this medicine may cause dizziness in some patients, who in such cases should not drive or operate dangerous machinery.

Megamilbedoce contains benzyl alcohol and sodium

This medicine must not be administered to premature infants or newborns because it contains 4 mg of benzyl alcohol per ampoule. Benzyl alcohol may cause toxic and allergic reactions in children under 3 years of age.

(See the section Children and adolescents in section 2. What you need to know...).

This medicine contains less than 23 mg (1 mmol) of sodium per ampoule and is therefore considered essentially “sodium-free”.

3. How to use Megamilbedoce

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

Recommended doses are:

Doses vary depending on the indication.

Intramuscular route, or in patients who have undergone gastrectomy (complete or partial removal of the stomach), by intramuscular route or deep subcutaneous route.

Adults

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

? The recommended initial dose is 100 micrograms of hydroxocobalamin (0.02 ml of solution) daily for 5–10 days, followed by 100–200 micrograms (0.02–0.04 ml of solution) monthly until improvement. After remission, a maintenance dose of 100 micrograms monthly 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) weekly until remission; maintenance dose of 1,000 micrograms every 2 or 3 months.

• Complicated pernicious anemia or vitamin B12 malabsorption with neurological complications (in the nervous system): the most common administration regimen is 1,000 micrograms of hydroxocobalamin (0.2 ml of injectable solution) daily during the first week of treatment, followed by 1,000 micrograms (0.2 ml) weekly for one month, and subsequently 1,000 micrograms (0.2 ml) monthly as maintenance dose until the underlying cause is resolved.

Patients with pernicious anemia or vitamin B12 deficiency due to another irreversible absorption defect 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.
• Vitamin B12 deficiency of dietary origin, as in strict vegetarians: a dose of 100 micrograms (0.02 ml) monthly by intramuscular route may be administered, with periodic blood tests.
• Metabolic disorders:
  • Methylmalonic acidemias with homocystinuria: The minimum dose to be administered is 1,000 micrograms (0.2 ml) daily by intramuscular route, which may be replaced by 1,000 micrograms (0.2 ml) administered on alternate days. If necessary, these doses may be increased up to double (up to 2,000 micrograms per administration, i.e., 0.4 ml of Megamilbedoce).
  • Methylmalonic acidemia without homocystinuria: Some cases improve with hydroxocobalamin at a dose of 1,000 micrograms (0.2 ml) weekly by intramuscular route. If no improvement is observed, your doctor will discontinue treatment.

Use in children

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

Requirements vary with age.

• In children with uncomplicated pernicious anemia or vitamin B12 malabsorption, the recommended dose is 30 to 50 micrograms daily (between 0.006 and 0.01 ml) for 2 or more weeks, up to a total dose of 1,000 to 5,000 micrograms of hydroxocobalamin (between 0.2 and 1 ml); this should be followed by a maintenance dose of 100 micrograms monthly (0.02 ml).
• 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, for a total of 5 doses; the maintenance dose is 1,000 micrograms every 3 months.
• Metabolic disorders:
  • Methylmalonic acidemias with homocystinuria: The minimum dose to be administered is 1,000 micrograms (0.2 ml) daily by intramuscular route, which may be replaced by 1,000 micrograms (0.2 ml) administered on alternate days. If necessary, these doses may be increased up to double (up to 2,000 micrograms per administration, i.e., 0.4 ml of Megamilbedoce). In younger children, a dose of 200 micrograms/kg body weight (0.04 ml/kg) daily is recommended.
  • Methylmalonic acidemia without homocystinuria: Some cases improve with hydroxocobalamin at a dose of 1,000 micrograms (0.2 ml) weekly by intramuscular route. If no improvement is observed, your doctor will discontinue treatment.

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

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

In methylmalonic acidemias 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 primarily administered by intramuscular route, and in patients who have undergone gastrectomy (complete or partial removal of the stomach), by intramuscular route or deep subcutaneous route.

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

• Oral route: can be administered orally in patients who do not tolerate the intramuscular route, provided they do not suffer from gastrointestinal disorders that seriously affect absorption. Oral absorption of hydroxocobalamin is irregular; therefore, monitoring through laboratory tests is required.

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

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

If you use more Megamilbedoce than you should

Even in accidental overdoses, cases of poisoning have not been reported. In rare instances, a severe allergic reaction may occur.

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

If you forget to use Megamilbedoce

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

If you forget to take your scheduled dose, take it as soon as possible.

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

4. Possible adverse effects

Like all medicines, Megamilbedoce may cause adverse effects, although not everyone experiences them.

These are generally uncommon, although moderately significant.

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

The following adverse effects may occur; the frequency of some of them is not exactly known:

• Frequently, reduction in the number of lymphocytes (a type of white blood cells).
• Possible masking of polycythaemia (a blood disorder).
• Uncommonly, pain at the injection site.
• Allergic reactions, with chest tightness, angioedema (rapid swelling of the skin, mucous membranes, and underlying tissues), urticaria (pink-red rash accompanied by burning or itching), pruritus, breathing difficulty; frequently, redness of the skin, skin eruptions (especially acne-like); photosensitivity (sensitivity to sunlight).
• Rarely, anaphylactic reaction (generalized allergic reaction).
• Decrease in blood potassium levels following injection of the medicine.
• Very frequently, headache.
• Restlessness, dizziness, swelling, eye irritation, and redness.
• Rarely, arrhythmias (irregular heartbeats).
• Congestive heart failure may occur at the beginning of treatment.
• Hot flushes, peripheral edema (swelling of ankles, feet, and legs); peripheral vascular thrombosis (formation of a clot obstructing circulation in a blood vessel outside the heart, usually in the legs or feet).
• With intravenous administration, hypervolemia (increased total blood volume) and

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

• Breathing difficulty or fatal "gasping syndrome" in premature infants due to benzyl alcohol content (see sections 2 and 3, "Megamilbedoce contains benzyl alcohol and sodium" and "Use in children"). Rarely, pulmonary edema (fluid infiltration into the lungs).
• Frequently, nausea.
• Gastrointestinal discomfort, transient diarrhea.
• Very frequently, reddish discoloration of urine.

If you experience any adverse effects, consult your doctor or pharmacist, even if they are adverse effects 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 expiry date stated on the packaging after EXP. The expiry date is the last day of the month indicated.

Medicines must not be disposed of via wastewater or household waste. Dispose of empty containers and unused medicines at the SIGRE Point located at your pharmacy. If you have any doubts, ask your pharmacist how to properly dispose of containers and medicines you no longer need. This will help protect the environment.

6. Package contents and other information

Composition of Megamilbedoce 10,000 micrograms Injectable Solution

• The active substance is hydroxocobalamin (vitamin B12).

One 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 injections.

Appearance of the medicine and contents of the pack

The medicine is a solution presented in topaz-coloured ampoules containing a clear red liquid.

Pack containing 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 most recent revision of this leaflet: November 2012

Other sources of information

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended only for doctors or healthcare professionals:

Intramuscular injection should be administered into a large muscle mass.

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