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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 08.04.2022
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Betolvex (cyanocobalamin) Nasal Spray is indicated for the maintenance of normal hematologic status in pernicious anemia patients who are in remission following intramuscular vitamin B12 therapy and who have no nervous system involvement.
Betolvex (cyanocobalamin) Nasal Spray is also indicated as a supplement for other vitamin B12 deficiencies, including:
I. Dietary deficiency of vitamin B12 occurring in strict vegetarians (Isolated vitamin B12 deficiency is very rare).
II. Malabsorption of vitamin B12 resulting from structural or functional damage to the stomach, where intrinsic factor is secreted, or to the ileum, where intrinsic factor facilitates vitamin B12 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 B12 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 B12 deficiency. Structural lesions leading to vitamin B12 deficiency include regional ileitis, ileal resections, malignancies, etc.
IV. Competition for vitamin B12 by intestinal parasites or bacteria. The fish tapeworm (Diphyllobothrium latum) absorbs huge quantities of vitamin B12 and infested patients often have associated gastric atrophy. The ">blind loop syndrome may produce deficiency of vitamin B12 or folate.
V. Inadequate utilization of vitamin B12. This may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia.
It may be possible to treat the underlying disease by surgical correction of anatomic lesions leading to small bowel bacterial overgrowth, expulsion of fish tapeworm, discontinuation of drugs leading to vitamin malabsorption (see Drug/Laboratory Test Interactions), use of a gluten free diet in nontropical sprue, or administration of antibiotics in tropical sprue. Such measures remove the need for long-term administration of vitamin B12.
Requirements of vitamin B12 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.
Betolvex (cyanocobalamin) Nasal Spray is not suitable for vitamin B12 absorption test (Schilling Test).
The recommended initial dose of Betolvex (cyanocobalamin) Nasal Spray is one spray (500 mcg) administered in ONE nostril once weekly. Betolvex (cyanocobalamin) Nasal Spray should be administered at least one hour before or one hour after ingestion of hot foods or liquids. Periodic monitoring of serum B12 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 cover and the 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 doses 2 through 8.
See LABORATORY TESTS for monitoring B12 levels and adjustment of dosage.
Sensitivity to cobalt and/or vitamin B12 or any component of the medication is a contraindication.
WARNINGS
Patients with early Leber's disease (hereditary optic nerve atrophy) who were treated with vitamin B12 suffered severe and swift optic atrophy.
Hypokalemia and sudden death may occur in severe megaloblastic anemia which is treated intensely with vitamin B12. Folic acid is not a substitute for vitamin B12 although it may improve vitamin B12-deficient megaloblastic anemia. Exclusive use of folic acid in treating vitamin B12-deficient megaloblastic anemia could result in progressive and irreversible neurologic damage.
Anaphylactic shock and death have been reported after parenteral vitamin B12 administration. No such reactions have been reported in clinical trials with Betolvex (cyanocobalamin) Nasal Spray or Betolvex (cyanocobalamin) Nasal Gel.
Blunted or impeded therapeutic response to vitamin B12 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.
PRECAUTIONS
General
An intradermal test dose of parenteral vitamin B12 is recommended before Betolvex (cyanocobalamin) Nasal Spray is administered to patients suspected of cyanocobalamin sensitivity. Vitamin B12 deficiency that is allowed to progress for longer than three months may produce permanent degenerative lesions of the spinal cord. Doses of folic acid greater than 0.1 mg per day may result in hematologic remission in patients with vitamin B12 deficiency. Neurologic manifestations will not be prevented with folic acid, and if not treated with vitamin B12, irreversible damage will result.
Doses of vitamin B12 exceeding 10 mcg daily may produce hematologic response in patients with folate deficiency. Indiscriminate administration may mask the true diagnosis.
The validity of diagnostic vitamin B12 or folic acid blood assays could be compromised by medications, and this should be considered before relying on such tests for therapy.
Vitamin B12 is not a substitute for folic acid and since it might improve folic acid deficient megaloblastic anemia, indiscriminate use of vitamin B12 could mask the true diagnosis.
Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic to normal erythropoiesis with vitamin B12 therapy. Therefore, serum potassium levels and the platelet count should be monitored carefully during therapy.
Vitamin B12 deficiency may suppress the signs of polycythemia vera. Treatment with vitamin B12 may unmask this condition.
If a patient is not properly maintained with Betolvex® (cyanocobalamin) Nasal Spray, intramuscular vitamin B12 is necessary for adequate treatment of the patient. No single regimen fits all cases, and the status of the patient observed in follow-up is the final criterion for adequacy of therapy.
The effectiveness of Betolvex (cyanocobalamin) Nasal Spray in patients with nasal congestion, allergic rhinitis and upper respiratory infections has not been determined. Therefore, treatment with Betolvex (cyanocobalamin) Nasal Spray should be deferred until symptoms have subsided.
Laboratory Tests
Hematocrit, reticulocyte count, vitamin B12, folate and iron levels should be obtained prior to treatment. If folate levels are low, folic acid should also be administered. All hematologic parameters should be normal when beginning treatment with Betolvex® (cyanocobalamin) Nasal Spray.
Vitamin B12 blood levels and peripheral blood counts must be monitored initially at one month after the start of treatment with Betolvex® (cyanocobalamin) Nasal Spray, and then at intervals of 3 to 6 months.
A decline in the serum levels of B12 after one month of treatment with B12 nasal spray may indicate that the dose may need to be adjusted upward. Patients should be seen one month after each dose adjustment; continued low levels of serum B12 may indicate that the patient is not a candidate for this mode of administration.
Patients with pernicious anemia have about 3 times the incidence of carcinoma of the stomach as in the general population, so appropriate tests for this condition should be carried out when indicated.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals to evaluate carcinogenic potential have not been done. There is no evidence from long-term use in patients with pernicious anemia that vitamin B12 is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this is believed to be related to the underlying pathology and not to treatment with vitamin B12.
Pregnancy
Pregnancy Category C: Animal reproduction studies have not been conducted with vitamin B12. It is also not known whether vitamin B12 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 B12 is an essential vitamin and requirements are increased during pregnancy. Amounts of vitamin B12 that are recommended by the Food and Nutrition Board, National Academy of Science - National Research Council for pregnant women should be consumed during pregnancy.
Nursing Mothers
Vitamin B12 appears in the milk of nursing mothers in concentrations which approximate the mother's vitamin B12 blood level. Amounts of vitamin B12 that are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for lactating women should be consumed during lactation.
Pediatric Use
Intake in pediatric patients should be in the amount recommended by the Food and Nutrition Board, National Academy of Science-National Research Council.
Please also see PATIENT INFORMATION
None.
Sensitisation to cyancobalamin is rare, but may present as an itching exanthema, and exceptionally as anaphylactic shock.
Acneform and bullous emptions have been reported rarely.
Patients who have become sensitised to Betolvex by injection are often able to tolerate cyancobalamin by the oral route without trouble.
Reporting of side effects
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below and in Table 1 reflect exposure in 25 subjects (age range 27-82 years; 17 women; 21 Caucasians) with vitamin B12 deficiency (12 with pernicious anemia, 4 secondary to gastrointestinal surgery, 9 with unknown cause) who received CaloMist Nasal Spray 50 mcg daily for 8 weeks in an uncontrolled clinical trial. Prior to enrollment, all subjects were required to have normal vitamin B12 levels with intramuscular vitamin BI2 injections. One patient who completed the study developed epistaxis on Day 12 of dosing and was noted to have irritation of the right nasal septum at study end. This patient had pre-existing allergic rhinitis and required a doubling of the CaloMist Nasal Spray dose during the last week of the study because of declining vitamin B12 concentrations.
Table 1. Potentially related adverse reactions reported during 8 weeks of treatment with CaloMist Nasal Spray in an uncontrolled clinical trial.
| Preferred Term | Betolvex Nasal Spray (cyanocobalamin) (N=25) n (%) |
| Arthralgia | 3 (12%) |
| Dizziness | 3 (12%) |
| Headache | 3 (12%) |
| Nasopharyngitis | 3 (12%) |
| Rhinorrhea | 3 (12%) |
| Bronchitis | 2 (8%) |
| Nasal Discomfort | 2 (8%) |
| Pain | 2 (8%) |
| Rash | 2 (8%) |
| Asthma | 1 (4%) |
| Back Pain | 1 (4%) |
| Cough | 1 (4%) |
| Epistaxis | 1 (4%) |
| Hypersomnia | 1 (4%) |
| Influenza Like Illness | 1 (4%) |
| Malaise | 1 (4%) |
| Pharyngolaryngeal Pain | 1 (4%) |
| Postnasal Drip | 1 (4%) |
| Procedural Pain | 1 (4%) |
| Pyrexia | 1 (4%) |
| Scab | 1 (4%) |
| Sinus Headache | 1 (4%) |
| Sinusitis | 1 (4%) |
| Tooth Abscess | 1 (4%) |
Experience with Parenteral Vitamin B12
The following adverse reactions have been reported with parenteral vitamin B12:
Generalized: Anaphylactic shock and death
Cardiovascular: Pulmonary edema and congestive heart failure early in treatment Peripheral vascular thrombosis
Hematological : Polycythemia vera
Gastrointestinal: Mild transient diarrhea Dermatological: Itching; transitory exanthema
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of cyanocobalamin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Angioedema and angioedema-like reactions
The incidence of adverse experiences described in the Table below are based on data from a short-term clinical trial in vitamin B12 deficient patients in hematologic remission receiving Betolvex (Cyanocobalamin, USP) Gel for Intranasal Administration (N=24) and intramuscular vitamin B12 (N=25). In the pharmacokinetic study comparing Betolvex (cyanocobalamin) Nasal Spray and Betolvex (cyanocobalamin) Nasal Gel, the incidence of adverse events was similar.
Table. Adverse Experiences by Body System, Number of Patients and Number of Occurrences by Treatment Following Intramuscular and Intranasal Administration of Cyanocobalamin.
| Number of Patients (Occurrences) | |||
| Body System | Adverse Experience | Vitamin B12 Nasal Gel, 500 mcg N=24 | Intramuscular Vitamin B12 , 100 mcg N=25 |
| Body as a Whole | Asthenia | 1 (1) | 4 (4) |
| Back Pain | 0 (0) | 1 (1) | |
| Generalized Pain | 0 (0) | 2 (3) | |
| Headache | 1 (2)* | 5 (11) | |
| Infectiona | 3 (4) | 3 (3) | |
| Cardiovascular System | Peripheral Vascular Disorder | 0 (0) | 1 (1) |
| Digestive System | Dyspepsia | 0 (0) | 1 (2) |
| Glossitis | 1 (1) | 0 (0) | |
| Nausea | 1 (1)* | 1 (1) | |
| Nausea & Vomiting | 0 (0) | 1 (1) | |
| Vomiting | 0 (0) | 1 (1) | |
| MusculoskeletalSystem | Arthritis | 0 (0) | 2 (2) |
| Myalgia | 0 (0) | 1 (1) | |
| Nervous System | Abnormal Gait | 0 (0) | 1 (1) |
| Anxiety | 0 (0) | 1 (1)* | |
| Dizziness | 0 (0) | 3 (3) | |
| Hypoesthesia | 0 (0) | 1 (1) | |
| Incoordination | 0 (0) | 1 (2)* | |
| Nervousness | 0 (0) | 1 (3)* | |
| Paresthesia | 1 (1) | 1 (1) | |
| Respiratory | Dyspnea | 0 (0) | 1 (1) |
| System | Rhinitis | 1 (1)* | 2 (2) |
| a Sore throat, common cold * There may be a possible relationship between these adverse experiences and the study drugs. These adverse experiences could have also been produced by the patient's clinical state or other concomitant therapy. |
The intensity of the reported adverse experiences following the administration of Betolvex (Cyanocobalamin, USP) Gel for Intranasal Administration and intramuscular vitamin B12 were generally mild. One patient reported severe headache following intramuscular dosing. Similarly, a few adverse experiences of moderate intensity were reported following intramuscular dosing (two headaches and rhinitis; one dyspepsia, arthritis, and dizziness), and dosing with Betolvex (Cyanocobalamin, USP) Gel for Intranasal Administration (one headache, infection, and paresthesia).
The majority of the reported adverse experiences following dosing with Betolvex (Cyanocobalamin, USP) Gel for Intranasal Administration and intramuscular vitamin B12 were judged to be intercurrent events. For the other reported adverse experiences, the relationship to study drug was judged as “possible” or “remote”. Of the adverse experiences judged to be of “possible” relationship to the study drug, anxiety, incoordination, and nervousness were reported following intramuscular vitamin B12 and headache, nausea, and rhinitis were reported following dosing with Betolvex (Cyanocobalamin, USP) Gel for Intranasal Administration.
The following adverse reactions have been reported with parenteral vitamin B12:
Generalized: Anaphylactic shock and death (See WARNINGS and PRECAUTIONS).
Cardiovascular: Pulmonary edema and congestive heart failure early in treatment; peripheral vascular thrombosis.
Hematological: Polycythemia vera.
Gastrointestinal: Mild transient diarrhea.
Dermatological: Itching; transitory exanthema.
Miscellaneous: Feeling of swelling of the entire body.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below and in Table 1 reflect exposure in 25 subjects (age range 27-82 years; 17 women; 21 Caucasians) with vitamin B12 deficiency (12 with pernicious anemia, 4 secondary to gastrointestinal surgery, 9 with unknown cause) who received CaloMist Nasal Spray 50 mcg daily for 8 weeks in an uncontrolled clinical trial. Prior to enrollment, all subjects were required to have normal vitamin B12 levels with intramuscular vitamin BI2 injections. One patient who completed the study developed epistaxis on Day 12 of dosing and was noted to have irritation of the right nasal septum at study end. This patient had pre-existing allergic rhinitis and required a doubling of the CaloMist Nasal Spray dose during the last week of the study because of declining vitamin B12 concentrations.
Table 1. Potentially related adverse reactions reported during 8 weeks of treatment with CaloMist Nasal Spray in an uncontrolled clinical trial.
| Preferred Term | CaloMist Nasal Spray (cyanocobalamin) (N=25) n (%) |
| Arthralgia | 3 (12%) |
| Dizziness | 3 (12%) |
| Headache | 3 (12%) |
| Nasopharyngitis | 3 (12%) |
| Rhinorrhea | 3 (12%) |
| Bronchitis | 2 (8%) |
| Nasal Discomfort | 2 (8%) |
| Pain | 2 (8%) |
| Rash | 2 (8%) |
| Asthma | 1 (4%) |
| Back Pain | 1 (4%) |
| Cough | 1 (4%) |
| Epistaxis | 1 (4%) |
| Hypersomnia | 1 (4%) |
| Influenza Like Illness | 1 (4%) |
| Malaise | 1 (4%) |
| Pharyngolaryngeal Pain | 1 (4%) |
| Postnasal Drip | 1 (4%) |
| Procedural Pain | 1 (4%) |
| Pyrexia | 1 (4%) |
| Scab | 1 (4%) |
| Sinus Headache | 1 (4%) |
| Sinusitis | 1 (4%) |
| Tooth Abscess | 1 (4%) |
Experience with Parenteral Vitamin B12
The following adverse reactions have been reported with parenteral vitamin B12:
Generalized: Anaphylactic shock and death
Cardiovascular: Pulmonary edema and congestive heart failure early in treatment Peripheral vascular thrombosis
Hematological : Polycythemia vera
Gastrointestinal: Mild transient diarrhea Dermatological: Itching; transitory exanthema
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of cyanocobalamin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Angioedema and angioedema-like reactions
No overdosage has been reported with Betolvex Nasal Spray, Betolvex (Cyanocobalamin, USP) Gel for Intranasal Administration or parenteral vitamin B12.
This medicine contains cyancobalamin vitamin B12, which is used for the treatment of pernicious anaemia, and nutritional deficiencies of vitamin B12 which results in macrocytic anaemia.
The absorption of cobalamins from the gut is dependent upon the glycoprotein intrinsic factor. Cobalamins are transported rapidly into the blood bound to protein, known as transcobalamins. Cobalamins are stored in the liver and excreted in the bile. They are known to cross the placenta.
Absorption
A three way crossover study in 25 fasting healthy subjects was conducted to compare the bioavailability of the B12 nasal spray to the B12 nasal gel and to evaluate the relative bioavailability of the nasal formulations as compared to the intramuscular injection. The peak concentrations after administration of intranasal spray were reached in 1.25 +/- 1.9 hours. The average peak concentration of B12 obtained after baseline correction following administration of intranasal spray was 757.96 +/- 532.17 pg/mL. The bioavailability of the nasal spray relative to the intramuscular injection was found to be 6.1%. The bioavailability of the B12 nasal spray was found to be 10% less than the B12 nasal gel. The 90% confidence intervals for the loge-transformed AUC(0-t) and Cmax was 71.71% - 114.19% and 71.6% - 118.66% respectively.
In pernicious anemia patients, once weekly intranasal dosing with 500 mcg B12 gel resulted in a consistent increase in pre-dose serum B12 levels during one month of treatment (p < 0.003) above that seen one month after 100 mcg intramuscular dose (Figure).
Distribution
In the blood, B12 is bound to transcobalamin II, a specific B-globulin carrier protein, and is distributed and stored primarily in the liver and bone marrow.
Elimination
About 3-8 mcg of B12 is secreted into the GI tract daily via the bile; in normal subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When B12 is administered in doses which saturate the binding capacity of plasma proteins and the liver, the unbound B12 is rapidly eliminated in the urine. Retention of B12 in the body is dose-dependent. About 80-90% of an intramuscular dose up to 50 mcg is retained in the body; this percentage drops to 55% for a 100 mcg dose, and decreases to 15% when a 1000 mcg dose is given.
| 12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses. " /> |
| Figure. Vitamin B12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses. |
Figure. Vitamin B12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses.
Medication GuidePATIENT INFORMATION
Patients with pernicious anemia should be instructed that they will require weekly intranasal administration of Betolvex (cyanocobalamin) 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 B12, 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 Betolvex (cyanocobalamin) 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 B12. Therefore, patients following such a diet should be advised to take Betolvex (cyanocobalamin) Nasal Spray weekly. The need for vitamin B12 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 B12 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 B12 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 safety clip, priming of the actuator and nasal administration of Betolvex (cyanocobalamin) 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.
No further relevant data.
None stated.
None
However, we will provide data for each active ingredient
