Vitamin B12a Other names: Hydroxocobalamin Hydroxycobalamin

Risk Summary

Available data from cases reported in the published literature and postmarketing surveillance with hydroxocobalamin use in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal and fetal outcomes. There are risks to the pregnant woman and fetus associated with untreated cyanide poisoning. In animal studies, hydroxocobalamin administered to pregnant rats and rabbits during the period of organogenesis caused skeletal and soft tissue abnormalities, including alterations in the central nervous system, at exposures similar to human exposures at the therapeutic dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Cyanide readily crosses the placenta. Cyanide poisoning is a medical emergency in pregnancy which can be fatal for the pregnant woman and fetus if left untreated. Life-sustaining therapy should not be withheld due to pregnancy.

Data

Animal Data

In animal studies, pregnant rats and rabbits received hydroxocobalamin (75, 150, or 300 mg/kg/d) during the period of organogenesis. Following intraperitoneal dosing in rats and intravenous dosing in rabbits, maternal exposures were equivalent to 0.5, 1, or 2 times the human exposure at the therapeutic dose (based on AUC). In the high dose groups for both species, maternal toxicity occurred, and there was a reduced number of live fetuses due to embryofetal resorptions. In addition, decreased live fetal weight occurred in high dose rats, but not in rabbits. Incomplete skeletal ossification occurred in both rats and rabbits. In rats, two fetuses of the high dose group and two fetuses of the mid dose group (each from a different litter) had short, rudimentary or small front or hind legs. Rabbit litters and fetuses exhibited a dose-dependent increase in various gross soft tissue and skeletal anomalies. The main findings in rabbits were flexed, rigid flexor or medially rotated forelimbs or hindlimbs and domed heads at external examination; enlarged anterior or posterior fontanelles of the ventricles of the brain and flat, bowed or large ribs at skeletal examination; and dilated ventricles of the brain, and thick wall of the stomach at visceral examination. It is unknown if similar findings would be observed in rats and rabbits if hydroxocobalamin was administered as a single dose during any critical period of development.

Risk Summary

Breastfeeding is not recommended during treatment with hydroxocobalamin. There are no data to determine when breastfeeding may be safely restarted following administration of hydroxocobalamin. Hydroxocobalamin and Vitamin B12 (which is formed when hydroxocobalamin combines with cyanide) are present in human milk. There are no data on the effects of hydroxocobalamin on the breastfed infant or the effects on milk production.

Carcinogenesis

Long-term animal studies have not been performed to evaluate the carcinogenic potential of hydroxocobalamin.

Mutagenesis

Hydroxocobalamin was negative in the following mutagenicity assays: in vitro bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli strains, an in vitro assay of the tk locus in mouse lymphoma cells, and an in vivo rat micronucleus assay.

Impairment of Fertility

The effect of hydroxocobalamin on fertility has not been evaluated.

Serious adverse reactions with hydroxocobalamin include allergic reactions, renal injury, and increases in blood pressure.

Clinical Trials Experience

Experience in Healthy Subjects

Because clinical trials were conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.

A double-blind, randomized, placebo-controlled, single-ascending-dose (2.5, 5, 7.5, and 10 g) study was conducted to assess the safety, tolerability, and pharmacokinetics of hydroxocobalamin in 136 healthy adult subjects. Because of the dark red color of hydroxocobalamin, the two most frequently occurring adverse reactions were chromaturia (red-colored urine) which was reported in all subjects receiving a 5 g dose or greater; and erythema (skin redness), which occurred in most subjects receiving a 5 g dose or greater. Adverse reactions reported in at least 5% of the 5 g dose group and corresponding rates in the 10 g and placebo groups are shown in Table 3.

Table 3. Incidence of Adverse Reactions Occurring in >5% of Subjects in 5 g Dose Group and Corresponding Incidence in 10 g Dose Group and Placebo:

* Rashes were predominantly acneiform

In this study, the following adverse reactions were reported to have occurred in a dose-dependent fashion and with greater frequency than observed in placebo-treated cohorts: increased blood pressure (particularly diastolic blood pressure), rash, nausea, headache and infusion site reactions. All were mild to moderate in severity and resolved spontaneously when the infusion was terminated or with standard supportive therapies.

Other adverse reactions reported in this study and considered clinically relevant were:

• Eye disorders: swelling, irritation, redness
• Gastrointestinal disorders: dysphagia, abdominal discomfort, vomiting, diarrhea, dyspepsia, hematochezia
• General disorders and administration site conditions: peripheral edema, chest discomfort
• Immune system disorders: allergic reaction
• Nervous system disorders: memory impairment, dizziness
• Psychiatric disorders: restlessness
• Respiratory, thoracic and mediastinal disorders: dyspnea, throat tightness, dry throat
• Skin and subcutaneous tissue disorders: urticaria, pruritus
• Vascular disorders: hot flush

Experience in Known or Suspected Cyanide Poisoning Victims

Four open-label, uncontrolled, clinical studies (one of which was prospective and three of which were retrospective) were conducted in known or suspected cyanide-poisoning victims. A total of 245 patients received hydroxocobalamin treatment in these studies. Systematic collection of adverse events was not done in all of these studies and interpretation of causality is limited due to the lack of a control group and due to circumstances of administration (e.g., use in fire victims). Adverse reactions reported in these studies listed by system organ class included:

• Cardiac disorders: ventricular extrasystoles
• Investigations: electrocardiogram repolarization abnormality, heart rate increased
• Respiratory, thoracic, and mediastinal disorders: pleural effusion

Adverse reactions common to both the studies in known or suspected cyanide poisoning victims and the study in healthy volunteers are listed in the healthy volunteer section only and are not duplicated in this list.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of hydroxocobalamin. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Cases of acute renal failure with acute tubular necrosis, renal impairment, and urine calcium oxalate crystals have been reported in patients treated with hydroxocobalamin.