{"adverse_reactions":["6 ADVERSE REACTIONS The most common adverse reactions (> 4%) were rhinorrhea, nasopharyngitis, arthralgia, dizziness, headache, nasal discomfort, pain, bronchitis, and rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fleming Pharmaceuticals at 1-800-343-0164 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 B 12 deficiency (12 with pernicious anemia, 4 secondary to gastrointestinal surgery, 9 with unknown cause) who received Calo Mist 50 mcg daily for 8 weeks in an uncontrolled clinical trial. Prior to enrollment, all subjects were required to have normal vitamin B 12 levels with intramuscular vitamin B 12 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 Calo Mist dose during the last week of the study because of declining vitamin B 12 concentrations. Table 1. Potentially related adverse reactions reported during 8 weeks of treatment with CaloMist in an uncontrolled clinical trial. Preferred Term Calo Mist (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%) 6.2 Experience with Parenteral Vitamin B 12 The following adverse reactions have been reported with parenteral vitamin B 12 : Generalized: Anaphylactic shock and death Cardiovascular: Pulmonary edema and congestive heart failure early in treatmentPeripheral vascular thrombosis Hematological Polycythemia vera Gastrointestinal: Mild transient diarrhea Dermatological: Itching; transitory exanthema 6.3 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 [ See Warnings and Precautions ( 5.4 ) ]."],"adverse_reactions_table":["
Table 1. Potentially related adverse reactions reported during 8 weeks of treatment with CaloMist in an uncontrolled clinical trial.
Preferred Term Calo Mist (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%)
","
Generalized: Anaphylactic shock and death
Cardiovascular: Pulmonary edema and congestive heart failure early in treatmentPeripheral vascular thrombosis
Hematological Polycythemia vera
Gastrointestinal: Mild transient diarrhea
Dermatological: Itching; transitory exanthema
"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There are no long-term studies in animals that have evaluated the carcinogenic potential of any of the vitamin B 12 products, including Calo Mist . There is no evidence from long-term use in patients with pernicious anemia that vitamin B 12 is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this malignancy has been attributed to the underlying pathology of pernicious anemia and not to treatment with vitamin B 12 ."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vitamin B 12 is essential for growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Rapidly dividing cells (e.g., epithelial cells, bone marrow, myeloid cells) have the greatest requirement for vitamin B 12 . In tissues, vitamin B 12 is essential for the conversion of methylmalonate to succinate and for the synthesis of methionine from homocysteine. In the absence of vitamin B 12 , tetrahydrofolate cannot be regenerated from 5-methyl tetrahydrofolate, and functional folate deficiency occurs. Vitamin B 12 also may be involved in sulfhydryl-activated enzyme systems associated with fat and carbohydrate metabolism and protein synthesis. 12.2 Pharmacodynamics In 24 vitamin B 12 deficient patients who were stabilized on intramuscular (IM) vitamin B 12 therapy, once daily intranasal dosing with Calo Mist for 8 weeks resulted in serum vitamin B 12 concentrations that were within the target range (>200 ng/L) and slightly higher than those seen 2 to 4 weeks after administration of IM vitamin B 12 (see Figure 1 - average mean increase from Visit 1 to Visits 3-6 = 45 ng/L). Twenty-three of these 24 patients received 50 mcg of Calo Mist daily for the duration of the trial; the remaining patient required doubling of the Calo Mist dose from 50 mcg to 100 mcg daily during the last week of the study because of declining vitamin B 12 concentrations. One of the 25 patients dosed with Calo Mist was excluded from the efficacy analyses because a diagnosis of vitamin B 12 deficiency could not be confirmed. Figure 1. Mean Vitamin B 12 Serum Levels Over 8 Weeks of Intranasal (IN) Vitamin B 12 Dosing in 24 Subjects Stabilized on Intramuscular (IM) Vitamin B 12 Notes: Weeks -2 to -4 correspond to 2 to 4 weeks post last IM injection Calo Mist was initiated at Week 0 Figure shows mean vitamin B 12 serum levels with 95% confidence intervals. 12.3 Pharmacokinetics Distribution In the blood, vitamin B 12 is bound to transcobalamin II (a specific B-globulin carrier protein) and is distributed to tissues and stored primarily in the liver and bone marrow. Elimination About 3-8 mcg of vitamin B 12 is secreted into the gastrointestinal tract daily via the bile. In subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When vitamin B 12 is administered in doses that saturate the binding capacity of plasma proteins and the liver, the unbound vitamin B 12 is rapidly eliminated in the urine. Retention of vitamin B 12 in the body is dose-dependent. mean vitamin b12 serum levels"],"contraindications":["4 CONTRAINDICATIONS Sensitivity to cobalt, vitamin B 12 , or any component of this product [ see Warnings and Precautions ( 5.4 ) ]. Sensitivity to cobalt, vitamin B 12 , or any component of this product (4)"],"description":["11 DESCRIPTION Cyanocobalamin is a synthetic form of vitamin B 12 with activity equivalent to the endogenous form of vitamin B 12 . The chemical name is α-(5,6-dimethylbenzimidazolyl) 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 1355.4 and the following structural formula: Cyanocobalamin occurs as dark red crystals, orthorhombic needles, or crystalline red powder and is very hygroscopic in the anhydrous form, and sparingly to moderately soluble in water (1:80). The pharmacologic activity of cyanocobalamin 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. Each bottle of Calo Mist contains cyanocobalamin, sodium chloride, sodium phosphate monobasic, benzyl alcohol, sodium hydroxide, and benzalkonium chloride in purified water with an attached spray pump unit. chemical structure"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION One spray in each nostril daily (25 mcg per nostril, total daily dose 50 mcg) (2.1) One spray in each nostril twice daily for patients with an inadequate response to once daily dosing (2.1) 2.1 Recommended Dose The recommended initial dose of Calo Mist is one spray in each nostril once daily (25 mcg per nostril, total daily dose 50 mcg). The dose should be increased to one spray in each nostril twice daily (total daily dose 100 mcg) for patients with an inadequate response to once daily dosing. The dosing of Calo Mist and other intranasal medications should be separated by several hours, and these patients should have more frequent monitoring of vitamin B 12 concentrations because of the potential for erratic absorption. 2.2 Priming (Activation) of Pump The pump must be primed before the bottle is used for the first time. To prime the pump, place the nozzle between the first and second finger with the thumb on the bottom of the bottle. Pump the unit firmly and quickly then repeat this priming an additional 6 times for a total of 7 priming sprays. Now the nasal spray is ready for first-time use. If 5 or more days elapse since last use, the pump must be re-primed with two re-priming sprays. Additional instructions are provided in the patient instruction sheet [ see Patient Counseling Information ( 17.2 ) ]."],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS Calo Mist (cyanocobalamin, USP) Nasal Spray is a solution of cyanocobalamin, USP, for administration as a metered spray to the nasal mucosa. Each bottle of Calo Mist contains 10.7 mL of a 25 mcg/0.1 mL solution of cyanocobalamin. The spray solution has a pH between 6.5 and 7.5. After initial priming, each spray delivers 25 mcg of cyanocobalamin. Each bottle will deliver 60 sprays for a total of thirty 50 mcg doses of Calo Mist . Nasal spray: 25 mcg cyanacobalamin, USP /0.1 mL (3)"],"drug_interactions":["7 DRUG INTERACTIONS Most antibiotics, methotrexate, and pyrimethamine invalidate the vitamin B 12 diagnostic blood assays."],"effective_time":"20100126","general_precautions":["5.1 Laboratory Monitoring Hematocrit, reticulocyte count, vitamin B 12 , folate, and iron levels should be obtained prior to treatment. All hematologic parameters, including vitamin B 12 concentrations, should be normal before initiating treatment with Calo Mist . Periodic monitoring of serum vitamin B 12 concentrations must be obtained to confirm adequacy of therapy. Vitamin B 12 concentrations and complete blood counts should be monitored one month after starting Calo Mist and then at 3 to 6 month intervals thereafter. Patients with borderline-low vitamin B 12 concentrations (<300 ng/L) should also undergo measurement of methylmalonic acid and homocysteine concentrations, which are more sensitive measures of vitamin B 12 deficiency in this setting. Patients with declining or abnormally low vitamin B 12 concentrations despite maximal doses of Calo Mist should be switched back to intramuscular vitamin B 12 injections. Vitamin B 12 deficiency that is inadequately treated for longer than three months may produce irreversible neurological damage."],"geriatric_use":["8.5 Geriatric Use Clinical studies of Calo Mist did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING Calo Mist is available as a metered dose spray in 30 mL plastic bottles containing 10.7 mL of solution. Calo Mist is available in a dosage strength of 25 mcg cyanocobalamin, USP, per actuation (0.1 mL/actuation). Calo Mist is provided in a carton containing one bottle of nasal spray solution affixed with a nasal spray pump, a package insert, and a patient instruction sheet. One bottle delivers thirty 50 mcg doses (60 sprays) (NDC 0256-0203-01). Storage Protect from light. Store upright at a controlled temperature of 15 to 30°C (59 to 86°F). Protect from freezing."],"id":"534a3a11-cdb6-46f2-ac20-9c290512e50c","indications_and_usage":["1 INDICATIONS AND USAGE Calo Mist is a vitamin B 12 indicated for: Maintenance of vitamin B 12 concentrations after normalization with intramuscular vitamin B 12 therapy in patients with vitamin B 12 deficiency who have no nervous system involvement (1.1) Important Limitations of Use: Calo Mist has not been evaluated for the treatment of newly diagnosed vitamin B 12 deficiency (1.2) 1.1 Vitamin B 12 Maintenance Therapy Calo Mist is indicated for maintenance of vitamin B 12 concentrations after normalization with intramuscular vitamin B 12 therapy in patients with vitamin B 12 deficiency who have no nervous system involvement. 1.2 Important Limitations of Use Calo Mist has not been evaluated for the treatment of newly diagnosed vitamin B 12 deficiency. Calo Mist is not suitable for use in the vitamin B 12 absorption test (Schilling Test). The effectiveness of Calo Mist in patients with nasal pathology (e.g., nasal congestion, allergic rhinitis, upper respiratory infections) has not been determined. Treatment with Calo Mist should be deferred until nasal symptoms have subsided [ see Warnings and Precautions ( 5.2 ) ]."],"information_for_patients":["17 PATIENT COUNSELING INFORMATION [ See FDA-approved Patient Labeling ( 17.2 ) ] 17.1 Important Information for Patients Patients with a chronic underlying cause of vitamin B 12 deficiency will require indefinite administration of a vitamin B 12 product, such as Calo Mist . Noncompliance or inadequate treatment with vitamin B 12 therapy may result in recurrence of anemia and the development or worsening of irreversible neurological damage. The dosing of Calo Mist and other intranasal medications should be separated by several hours. Vitamin B 12 concentrations should be monitored one month after Calo Mist initiation or dose change and every 3-6 months thereafter. Careful instructions on the priming of the actuator and nasal administration of Calo Mist should be given to the patient, and the procedures for use should be demonstrated. 17.2 Patient Instruction Sheet Instructions for Using Calo Mist . Read the following instructions carefully before using Calo Mist . Use Calo Mist as directed by your doctor. NOTE: Calo Mist is prefilled to give 30 doses (60 sprays of medicine). One dose is one spray in each nostril once a day. Calo Mist Pump Priming: Before you use the medicine for the first time the nasal spray pump unit must be readied (primed). 1. Hold the nasal spray bottle upright with your index finger on top of one of the two arms of the pump. Remove the clear protective cap from the top of the nozzle. ( See Diagram 1 ) 2. Remove the safety clip from the nasal spray pump. ( See Diagram 1) 3. While holding the nasal spray bottle upright with your index and middle fingers on the two side arms of the pump, and your thumb on the bottom of the bottle, press the arms down firmly and quickly. ( See Diagram 2 ) 4. Repeat Step 3, 6 more times for a total of 7 priming sprays. You should see a full spray of medicine with the 7 th priming spray. ( See Diagram 2 ) NOTE: You must prime Calo Mist with two re-priming sprays if you do not use for five days or more. Your Calo Mist is now ready to use. 1. Blow your nose gently to clear both nostrils. ( See Diagram 3 ) 2. Hold the nasal spray bottle upright with your first and second fingers on the two side arms of the pump. Place your thumb on the bottom of the bottle. ( See Diagram 4 ) 3. Gently insert the nasal spray pump into one nostril (about ½ inch), pointing the tip towards the back of the nose. ( See Diagram 4) 4. With your other hand (the one not holding the bottle) use a finger to gently push close your other nostril (the one without a spray pump inserted). ( See Diagram 4 ) 5. Tilt your head forward. Firmly and quickly press down the arms of the nasal spray bottle. 6. Sniff in gently during and right after a spray and return your head to an upright position. Repeat these steps for the other nostril. 7. After use, wipe the nozzle of the nasal spray pump with a clean tissue. Replace the safety clip and clear cover on the nasal spray pump. 8. Store Calo Mist upright at room temperature, 15° - 30° C (59° - 86° F). Do not freeze. Discard Calo Mist after 30 doses (60 sprays). Unscrew the cap. Rinse the bottle and pump assembly under a water faucet. Dispose of all parts in a trashcan. Keep Calo Mist and all medicines out of the reach of children. Manufactured by: Fleming Pharmaceuticals St. Louis County, MO 63026 USA calomist@flemingpharma.com 1-800-343-0164 pump priming diagram diagram 2 diagram 3 diagram 4"],"mechanism_of_action":["12.1 Mechanism of Action Vitamin B 12 is essential for growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Rapidly dividing cells (e.g., epithelial cells, bone marrow, myeloid cells) have the greatest requirement for vitamin B 12 . In tissues, vitamin B 12 is essential for the conversion of methylmalonate to succinate and for the synthesis of methionine from homocysteine. In the absence of vitamin B 12 , tetrahydrofolate cannot be regenerated from 5-methyl tetrahydrofolate, and functional folate deficiency occurs. Vitamin B 12 also may be involved in sulfhydryl-activated enzyme systems associated with fat and carbohydrate metabolism and protein synthesis."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There are no long-term studies in animals that have evaluated the carcinogenic potential of any of the vitamin B 12 products, including Calo Mist . There is no evidence from long-term use in patients with pernicious anemia that vitamin B 12 is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this malignancy has been attributed to the underlying pathology of pernicious anemia and not to treatment with vitamin B 12 ."],"nursing_mothers":["8.3 Nursing Mothers Although vitamin B 12 is an essential vitamin and requirements are increased during lactation, it is not known whether Calo Mist can cause harm to an infant when administered to a nursing woman. Vitamin B 12 appears in the milk of nursing mothers in concentrations that approximate the mother's vitamin B 12 blood level. Caution should be exercised when Calo Mist is administered to a nursing woman."],"openfda":{},"package_label_principal_display_panel":["Principal Display Panel - carton principal display panel - carton principal display panel - carton","Principal Display Panel - bottle principal display panel - bottle principal display panel - bottle"],"pediatric_use":["8.4 Pediatric Use Because Calo Mist has not been studied in children, safety and effectiveness have not been established in pediatric patients."],"pharmacodynamics":["12.2 Pharmacodynamics In 24 vitamin B 12 deficient patients who were stabilized on intramuscular (IM) vitamin B 12 therapy, once daily intranasal dosing with Calo Mist for 8 weeks resulted in serum vitamin B 12 concentrations that were within the target range (>200 ng/L) and slightly higher than those seen 2 to 4 weeks after administration of IM vitamin B 12 (see Figure 1 - average mean increase from Visit 1 to Visits 3-6 = 45 ng/L). Twenty-three of these 24 patients received 50 mcg of Calo Mist daily for the duration of the trial; the remaining patient required doubling of the Calo Mist dose from 50 mcg to 100 mcg daily during the last week of the study because of declining vitamin B 12 concentrations. One of the 25 patients dosed with Calo Mist was excluded from the efficacy analyses because a diagnosis of vitamin B 12 deficiency could not be confirmed. Figure 1. Mean Vitamin B 12 Serum Levels Over 8 Weeks of Intranasal (IN) Vitamin B 12 Dosing in 24 Subjects Stabilized on Intramuscular (IM) Vitamin B 12 Notes: Weeks -2 to -4 correspond to 2 to 4 weeks post last IM injection Calo Mist was initiated at Week 0 Figure shows mean vitamin B 12 serum levels with 95% confidence intervals."],"pharmacokinetics":["12.3 Pharmacokinetics Distribution In the blood, vitamin B 12 is bound to transcobalamin II (a specific B-globulin carrier protein) and is distributed to tissues and stored primarily in the liver and bone marrow. Elimination About 3-8 mcg of vitamin B 12 is secreted into the gastrointestinal tract daily via the bile. In subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When vitamin B 12 is administered in doses that saturate the binding capacity of plasma proteins and the liver, the unbound vitamin B 12 is rapidly eliminated in the urine. Retention of vitamin B 12 in the body is dose-dependent."],"pregnancy":["8.1 Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with Calo Mist . Although vitamin B 12 is an essential vitamin and requirements are increased during pregnancy, it is not known whether Calo Mist can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Calo Mist should be given to a pregnant woman only if clearly needed. Adequate and well-controlled studies have not been conducted in pregnant women."],"recent_major_changes":["Dosage Forms and Strengths (3) 6/2008"],"set_id":"e9a22b33-a629-4fcf-8f59-54633670a945","spl_product_data_elements":["CaloMist cyanocobalamin CYANOCOBALAMIN CYANOCOBALAMIN SODIUM CHLORIDE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE BENZYL ALCOHOL SODIUM HYDROXIDE BENZALKONIUM CHLORIDE WATER"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS Patients with vitamin B 12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of vitamin B 12 therapy ( 8.6 ) 8.1 Pregnancy Pregnancy Category C: Animal reproduction studies have not been conducted with Calo Mist . Although vitamin B 12 is an essential vitamin and requirements are increased during pregnancy, it is not known whether Calo Mist can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Calo Mist should be given to a pregnant woman only if clearly needed. Adequate and well-controlled studies have not been conducted in pregnant women. 8.3 Nursing Mothers Although vitamin B 12 is an essential vitamin and requirements are increased during lactation, it is not known whether Calo Mist can cause harm to an infant when administered to a nursing woman. Vitamin B 12 appears in the milk of nursing mothers in concentrations that approximate the mother's vitamin B 12 blood level. Caution should be exercised when Calo Mist is administered to a nursing woman. 8.4 Pediatric Use Because Calo Mist has not been studied in children, safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of Calo Mist did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal/Hepatic Impairment Patients with vitamin B 12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of vitamin B 12 therapy."],"version":"2","warnings_and_cautions":["5 WARNINGS AND PRECAUTIONS Vitamin B 12 concentrations must be monitored. Patients with declining or abnormally low vitamin B 12 concentrations should be switched back to intramuscular vitamin B 12 injections (5.1) . Effectiveness in patients with nasal pathology or with other concomitant intranasal drugs has not been determined. Use with caution ( 5.2 ) Cyanocobalamin causes optic nerve atrophy in patients with Leber’s disease. Do not use ( 5.3 ) Anaphylaxis and angioedema have been reported with parenteral vitamin B 12 products ( 5.4 ) 5.1 Laboratory Monitoring Hematocrit, reticulocyte count, vitamin B 12 , folate, and iron levels should be obtained prior to treatment. All hematologic parameters, including vitamin B 12 concentrations, should be normal before initiating treatment with Calo Mist . Periodic monitoring of serum vitamin B 12 concentrations must be obtained to confirm adequacy of therapy. Vitamin B 12 concentrations and complete blood counts should be monitored one month after starting Calo Mist and then at 3 to 6 month intervals thereafter. Patients with borderline-low vitamin B 12 concentrations (<300 ng/L) should also undergo measurement of methylmalonic acid and homocysteine concentrations, which are more sensitive measures of vitamin B 12 deficiency in this setting. Patients with declining or abnormally low vitamin B 12 concentrations despite maximal doses of Calo Mist should be switched back to intramuscular vitamin B 12 injections. Vitamin B 12 deficiency that is inadequately treated for longer than three months may produce irreversible neurological damage. 5.2 Use in Patients With Nasal Pathology Calo Mist has not been evaluated in patients with nasal pathology. Treatment with Calo Mist should be deferred until nasal symptoms have subsided. Patients with chronic nasal symptoms or significant nasal pathology are not ideal candidates for intranasal vitamin B 12 therapy. If Calo Mist therapy is attempted in these patients, vitamin B 12 concentrations should be monitored more frequently than in patients without nasal pathology because of the potential for erratic or blunted absorption. 5.3 Use in Patients with Leber’s Disease Patients with early Leber’s disease (hereditary optic nerve atrophy) who were treated with cyanocobalamin suffered severe and swift optic atrophy. Cyanocobalamin should not be used in these patients. 5.4 Anaphylaxis and Angioedema Anaphylactic shock, death, and angioedema were not reported in the Calo Mist clinical trial but have been reported with parenteral vitamin B 12 administration. 5.5 Megaloblastic Anemia Megaloblastic anemia has many causes, including vitamin B 12 deficiency and folate deficiency. Folic acid may result in a hematological response in patients with vitamin B 12 deficiency, but will not prevent irreversible neurological manifestations. Vitamin B 12 is not an appropriate treatment for folate deficiency. Hypokalemia, thrombocytosis, and sudden death may occur when severe megaloblastic anemia is treated intensely with vitamin B 12 . Serum potassium and the platelet count should be carefully monitored in this setting. 5.6 Blunted Response to Vitamin B 12 Therapy Infections, uremia, concurrent iron or folic acid deficiency, and drugs with bone marrow suppressant properties (e.g., chloramphenicol) may blunt the therapeutic response to vitamin B 12 products, including Calo Mist ."]}