vitamin B 12 500 MCG/ACTUAT Nasal Spray
WARNINGS
Patients with early Leber’s disease (hereditary optic nerve atrophy) who were treated with vitamin B 12 suffered severe and swift optic atrophy.
Hypokalemia and sudden death may occur in severe megaloblastic anemia which is treated intensely with vitamin B 12 .
Folic acid is not a substitute for vitamin B 12 although it may improve vitamin B 12 -deficient megaloblastic anemia.
Exclusive use of folic acid in treating vitamin B 12 -deficient megaloblastic anemia could result in progressive and irreversible neurologic damage.
Anaphylactic shock and death have been reported after parenteral vitamin B 12 administration.
No such reactions have been reported in clinical trials with Nascobal Nasal Spray or Nascobal Nasal Gel.
Blunted or impeded therapeutic response to vitamin B 12 may be due to such conditions as infection, uremia, drugs having bone marrow suppressant properties such as chloramphenicol, and concurrent iron or folic acid deficiency.
OVERDOSAGE
No overdosage has been reported with Nascobal Nasal Spray, Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration or parenteral vitamin B 12 .
DESCRIPTION
Cyanocobalamin is a synthetic form of vitamin B 12 with equivalent vitamin B 12 activity.
The chemical name is 5,6-dimethyl-benzimidazolyl cyanocobamide.
The cobalt content is 4.35%.
The molecular formula is C 63 H 88 CoN 14 O 14 P, which corresponds to a molecular weight of 1355.38 and the following structural formula: Cyanocobalamin occurs as dark red crystals or orthorhombic needles or crystalline red powder.
It is very hygroscopic in the anhydrous form, and sparingly to moderately soluble in water (1:80).
Its pharmacologic activity is destroyed by heavy metals (iron) and strong oxidizing or reducing agents (vitamin C), but not by autoclaving for short periods of time (15-20 minutes) at 121°C.
The vitamin B 12 coenzymes are very unstable in light.
Nascobal® Nasal Spray is a solution of Cyanocobalamin, USP (vitamin B12 ) for administration as a spray to the nasal mucosa.
Each bottle of Nascobal Nasal Spray contains 1.3mL of a 500 mcg/0.1mL solution of cyanocobalamin with sodium citrate, citric acid, and glycerin and benzalkonium chloride in purified water.
The spray solution has a pH between 4.5 and 5.5.
The spray pump unit must be fully primed (see Dosage and Administration) prior to initial use.
After initial priming, each spray delivers an average of 500 mcg of cyanocobalamin and the 1.3mL of spray solution contained in the bottle will deliver 4 doses of Nascobal Nasal Spray.
The unit must be re-primed before each dose.
(see Dosage and Administration).
chemical structure
HOW SUPPLIED
Nascobal Nasal Spray is available as a spray in 3 mL glass bottles containing 1.3 mL of solution.
It is available in a dosage strength of 500 mcg per actuation (0.1 mL/actuation).
A screw-on actuator is provided.
This actuator, following priming, will deliver 0.1 mL of the spray.
Nascobal Nasal Spray is provided in a carton containing a nasal spray actuator with dust cover, a bottle of nasal spray solution, and a package insert.
One bottle will deliver 4 doses (NDC 49884-270-86).
PHARMACIST ASSEMBLY INSTRUCTIONS FOR NASCOBAL NASAL SPRAY The pharmacist should assemble the Nascobal Nasal Spray unit prior to dispensing to the patient, according to the following instructions: 1.
Open the carton and remove the spray actuator and spray solution bottle.
2.
Assemble Nascobal Nasal Spray by first unscrewing the white cap from the spray solution bottle and screwing the actuator unit tightly onto the bottle.
Make sure the clear dust cover is on the pump unit.
3.
Return the Nascobal Nasal Spray bottle to the carton for dispensing to the patient.
Bottle Instructions
MECHANISM OF ACTION
GENERAL PHARMACOLOGY AND Vitamin B 12 is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis.
Cells characterized by rapid division (e.g., epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for vitamin B 12 .
Vitamin B 12 can be converted to coenzyme B 12 in tissues, and as such is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine, a reaction which also requires folate.
In the absence of coenzyme B 12 , tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyltetrahydrofolate, and a functional folate deficiency occurs.
Vitamin B 12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems.
Through these reactions, vitamin B 12 is associated with fat and carbohydrate metabolism and protein synthesis.
Vitamin B 12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage that begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head.
Cyanocobalamin is the most stable and widely used form of vitamin B 12 , and has hematopoietic activity apparently identical to that of the antianemia factor in purified liver extract.
The information below, describing the clinical pharmacology of cyanocobalamin, has been derived from studies with injectable vitamin B 12 .
Vitamin B 12 is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of injection.
It is bound to plasma proteins and stored in the liver.
Vitamin B 12 is excreted in the bile and undergoes some enterohepatic recycling.
Absorbed vitamin B 12 is transported via specific B 12 binding proteins, transcobalamin I and II, to the various tissues.
The liver is the main organ for vitamin B 12 storage.
Parenteral (intramuscular) administration of vitamin B 12 completely reverses the megaloblastic anemia and GI symptoms of vitamin B 12 deficiency; the degree of improvement in neurologic symptoms depends on the duration and severity of the lesions, although progression of the lesions is immediately arrested.
Gastrointestinal absorption of vitamin B 12 depends on the presence of sufficient intrinsic factor and calcium ions.
Intrinsic factor deficiency causes pernicious anemia, which may be associated with subacute combined degeneration of the spinal cord.
Prompt parenteral administration of vitamin B 12 prevents progression of neurologic damage.
The average diet supplies about 4 to 15 mcg/day of vitamin B 12 in a protein-bound form that is available for absorption after normal digestion.
Vitamin B 12 is not present in foods of plant origin, but is abundant in foods of animal origin.
In people with normal absorption, deficiencies have been reported only in strict vegetarians who consume no products of animal origin (including no milk products or eggs).
Vitamin B 12 is bound to intrinsic factor during transit through the stomach; separation occurs in the terminal ileum in the presence of calcium, and vitamin B 12 enters the mucosal cell for absorption.
It is then transported by the transcobalamin binding proteins.
A small amount (approximately 1% of the total amount ingested) is absorbed by simple diffusion, but this mechanism is adequate only with very large doses.
Oral absorption is considered too undependable to rely on in patients with pernicious anemia or other conditions resulting in malabsorption of vitamin B 12 .
Colchicine, para-aminosalicylic acid, and heavy alcohol intake for longer than 2 weeks may produce malabsorption of vitamin B 12 .
INDICATIONS AND USAGE
Nascobal Nasal Spray is indicated for the maintenance of normal hematologic status in pernicious anemia patients who are in remission following intramuscular vitamin B 12 therapy and who have no nervous system involvement.
Nascobal Nasal Spray is also indicated as a supplement for other vitamin B 12 deficiencies, including: I.
Dietary deficiency of vitamin B 12 occurring in strict vegetarians (Isolated vitamin B 12 deficiency is very rare).
II.
Malabsorption of vitamin B 12 resulting from structural or functional damage to the stomach, where intrinsic factor is secreted, or to the ileum, where intrinsic factor facilitates vitamin B 12 absorption.
These conditions include HIV infection, AIDS, Crohn’s disease, tropical sprue, and nontropical sprue (idiopathic steatorrhea, gluten-induced enteropathy).
Folate deficiency in these patients is usually more severe than vitamin B 12 deficiency.
III.
Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric mucosa (ingestion of corrosives, extensive neoplasia), and a number of conditions associated with a variable degree of gastric atrophy (such as multiple sclerosis, HIV infection, AIDS, certain endocrine disorders, iron deficiency, and subtotal gastrectomy).
Total gastrectomy always produces vitamin B 12 deficiency.
Structural lesions leading to vitamin B 12 deficiency include regional ileitis, ileal resections, malignancies, etc.
IV.
Competition for vitamin B 12 by intestinal parasites or bacteria.
The fish tapeworm (Diphyllobothrium latum) absorbs huge quantities of vitamin B 12 and infested patients often have associated gastric atrophy.
The blind loop syndrome may produce deficiency of vitamin B 12 or folate.
V.
Inadequate utilization of vitamin B 12 .
This may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia.
Requirements of vitamin B 12 in excess of normal (due to pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic and renal disease) can usually be met with intranasal or oral supplementation.
Nascobal Nasal Spray is not suitable for vitamin B 12 absorption test (Schilling Test).
PEDIATRIC USE
8.
Intake in pediatric patients should be in the amount recommended by the Food and Nutrition Board, National Academy of Science-National Research Council.
PREGNANCY
6.
Pregnancy Category C: Animal reproduction studies have not been conducted with vitamin B 12 .
It is also not known whether vitamin B 12 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Adequate and well-controlled studies have not been done in pregnant women.
However, vitamin B 12 is an essential vitamin and requirements are increased during pregnancy.
Amounts of vitamin B 12 that are recommended by the Food and Nutrition Board, National Academy of Science – National Research Council for pregnant women should be consumed during pregnancy.
NUSRING MOTHERS
7.
NURSING MOTHERS Vitamin B 12 appears in the milk of nursing mothers in concentrations which approximate the mother’s vitamin B 12 blood level.
Amounts of vitamin B 12 that are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for lactating women should be consumed during lactation.
INFORMATION FOR PATIENTS
2.
Patients with pernicious anemia should be instructed that they will require weekly intranasal administration of Nascobal Nasal Spray for the remainder of their lives.
Failure to do so will result in return of the anemia and in development of incapacitating and irreversible damage to the nerves of the spinal cord.
Also, patients should be warned about the danger of taking folic acid in place of vitamin B 12 , because the former may prevent anemia but allow progression of subacute combined degeneration of the spinal cord.
(Hot foods may cause nasal secretions and a resulting loss of medication; therefore, patients should be told to administer Nascobal Nasal Spray at least one hour before or one hour after ingestion of hot foods or liquids.) A vegetarian diet which contains no animal products (including milk products or eggs) does not supply any vitamin B 12 .
Therefore, patients following such a diet should be advised to take Nascobal Nasal Spray weekly.
The need for vitamin B 12 is increased by pregnancy and lactation.
Deficiency has been recognized in infants of vegetarian mothers who were breast fed, even though the mothers had no symptoms of deficiency at the time.
Because the nasal dosage forms of vitamin B 12 have a lower absorption than intramuscular dosage, nasal dosage forms are administered weekly, rather than the monthly intramuscular dosage.
As shown in the Figure above, at the end of a month, weekly nasal administration results in significantly higher serum vitamin B 12 levels than after intramuscular administration.
The patient should also understand the importance of returning for follow-up blood tests every 3 to 6 months to confirm adequacy of the therapy.
Careful instructions on the actuator assembly, removal of the safety clip, priming of the actuator and nasal administration of Nascobal Nasal Spray should be given to the patient.
Although instructions for patients are supplied with individual bottles, procedures for use should be demonstrated to each patient.
DOSAGE AND ADMINISTRATION
The recommended initial dose of Nascobal Nasal Spray is one spray (500 mcg) administered in ONE nostril once weekly.
Nascobal Nasal Spray should be administered at least one hour before or one hour after ingestion of hot foods or liquids.
Periodic monitoring of serum B 12 levels should be obtained to establish adequacy of therapy.
Priming (Activation) of Pump Before the first dose and administration, the pump must be primed.
Remove the clear plastic safety clip from the pump.
To prime the pump, place nozzle between the first and second finger with the thumb on the bottom of the bottle.
Pump the unit firmly and quickly until the first appearance of spray.
Then prime the pump an additional 2 times.
Now the nasal spray is ready for use.
The unit must be re-primed before each dose.
Prime the pump once immediately before each administration of dose 2 through 4.
See LABORATORY TESTS for monitoring B 12 levels and adjustment of dosage.
Priming the Bottle