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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 .
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 ) ].