CYANOKIT (hydroxocobalamin for injection)

In conjunction with CYANOKIT, treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of oxygenation and hydration, cardiovascular support, and management of seizures. Consideration should be given to decontamination measures based on the route of exposure. Use caution in the management of patients with known anaphylactic reactions to hydroxocobalamin or cyanocobalamin. Consider alternative therapies, if available.

Allergic reactions may include: anaphylaxis, chest tightness, edema, urticaria, pruritus, dyspnea, and rash. Allergic reactions including angioneurotic edema have also been reported in postmarketing experience.

Cases of acute renal failure with acute tubular necrosis, renal impairment, and urine calcium oxalate crystals have been reported. In some situations, hemodialysis was required to achieve recovery. Regular monitoring of renal function, including but not limited to blood urea nitrogen (BUN) and serum creatinine, should be performed for 7 days following CYANOKIT therapy.

Many patients with cyanide poisoning will be hypotensive; however, elevations in blood pressure have also been observed in known or suspected cyanide poisoning victims. Elevations in blood pressure (≥180 mmHg systolic or ≥110 mmHg diastolic) were observed in approximately 18% of healthy subjects (not exposed to cyanide) receiving hydroxocobalamin 5 g and 28% of subjects receiving 10 g. Increases in blood pressure were noted shortly after the infusions were started; the maximal increase in blood pressure was observed toward the end of the infusion. These elevations were generally transient and returned to baseline levels within 4 hours of dosing. Monitor blood pressure during treatment with CYANOKIT.

Because of its deep red color, hydroxocobalamin has been found to interfere with colorimetric determination of certain laboratory parameters (e.g., clinical chemistry, hematology, coagulation, and urine parameters).

Also because of its deep red color, hydroxocobalamin may cause hemodialysis machines to shut down due to an erroneous detection of a "blood leak." This should be considered before hemodialysis is initiated in patients treated with hydroxocobalamin.

While it is not known if the skin redness predisposes to photosensitivity, patients should be advised to avoid direct sun while their skin remains discolored.

Most common adverse reactions (>5%) include transient chromaturia, erythema, oxalate crystals in urine, rash, increased blood pressure, nausea, headache, and infusion site reactions.

Available data from cases reported in the published literature and postmarketing surveillance with CYANOKIT 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.

Breastfeeding is not recommended during treatment with CYANOKIT.

DuoDote^® Auto-Injector (atropine and pralidoxime chloride injection), for intramuscular use

There are no contraindications to the use of DuoDote.

Cardiovascular risks include tachycardia, palpitations, premature ventricular contractions, flutter, fibrillation, asystole, and myocardial infarction. Other cardiovascular adverse reactions have also been reported. Use caution in patients with known CV disease or conduction problems.

Heat injury may occur. Atropine may inhibit sweating and lead to hyperthermia. Avoid excessive exercising and heat exposure.

Acute glaucoma may be precipitated in susceptible individuals, and therefore DuoDote should be administered with caution in patients at risk for acute glaucoma.

Administer with caution in patients with bladder outflow obstruction as urinary retention may occur.

DuoDote should be administered with caution in patients with partial pyloric stenosis because of the risk of complete pyloric obstruction.

Atropine may cause inspiration of bronchial secretions and formation of dangerous viscid plugs and may exacerbate chronic lung disease. Monitor respiratory status.

Common adverse reactions of atropine include dryness of the mouth, blurred vision, dry eyes, photophobia, confusion, headache, and dizziness, among others. The common adverse reactions of pralidoxime chloride include changes in vision, dizziness, headache, drowsiness, nausea, tachycardia, increased blood pressure, muscular weakness, dry mouth, emesis, rash, dry skin, hyperventilation, decreased renal function, excitement, manic behavior, and transient elevation of liver enzymes and creatine phosphokinase.

Muscle tightness and pain may occur at the injection site.

Patients who have received succinylcholine and mivacurium may exhibit an accelerated reversal of the neuromuscular blocking effects when treated with DuoDote. Monitor neuromuscular effects with concomitant administration.

Safety and effectiveness of DuoDote in pediatric patients weighing less than or equal to 41 kg (90 pounds) have not been established.

Geriatric patients may be more susceptible to the effects of atropine.

Pralidoxime chloride can cause decreased renal function. Patients with severe renal impairment may require less frequent doses after the initial dose.

Patients with severe hepatic impairment may require less frequent doses after the initial dose. 

IMPORTANT SAFETY INFORMATION

SEIZALAM is contraindicated in patients with a known hypersensitivity to midazolam.

Concomitant use of benzodiazepines, including SEIZALAM, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation.  Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.

The use of benzodiazepines, including SEIZALAM, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death.

Before prescribing SEIZALAM and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of SEIZALAM, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SEIZALAM along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue SEIZALAM (a patient-specific plan should be used to taper the dose).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

The continued use of benzodiazepines may lead to clinically significant physical dependence. Although SEIZALAM is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of SEIZALAM, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures).

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations, particularly in patients with hemodynamic instability. Hypotension occurs more frequently in patients premedicated with a narcotic. The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve; patients with COPD are highly sensitive to the respiratory depressant effect of midazolam. SEIZALAM should be administered with caution to patients in shock or coma with depression of vital signs. Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness have been reported with midazolam when used for sedation. These reactions may be caused by inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Agitation also occurred in the randomized controlled clinical study of SEIZALAM in patients with status epilepticus.

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. SEIZALAM should be administered with caution to patients in acute alcohol intoxication with depression of vital signs. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the central nervous system (CNS). Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions.

Midazolam is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits.

Benzodiazepines, including SEIZALAM, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with SEIZALAM. SEIZALAM is not recommended in patients with narrow-angle glaucoma.

SEIZALAM is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol‑preserved drugs, including SEIZALAM. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (SEIZALAM contains 10 mg of benzyl alcohol per mL).

Caution is advised when SEIZALAM is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole). These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam.

Geriatric patients may have altered drug distribution; diminished hepatic and/or renal function; longer elimination half-lives for midazolam and its metabolites, and subjects over 70 years of age may be particularly sensitive. Administration of IM midazolam to elderly patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression.  In most of these cases, the patients received other central nervous system depressants capable of depressing respiration, especially narcotics. Close monitoring of geriatric patients is recommended.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs during pregnancy. Encourage women who are taking SEIZALAM during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

The manifestations of midazolam overdosage are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and untoward effects on vital signs. Treatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen.  Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk patients. Its use in patients with epilepsy is typically not recommended.