WARNING: ABUSE AND DEPENDENCE CNS stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence. ( 5.1 ) WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. CNS stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence. ( 5.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS NUMBRINO is for TOPICAL USE ONLY. NOT FOR INJECTION OR OPHTHALMIC USE. ( 5 ) Seizures: NUMBRINO may lower the convulsive threshold. Monitor patients for development of seizures. Blood Pressure and Heart Rate Increases: Monitor vital signs, including heart rate and rhythm, in patients after receiving NUMBRINO. Avoid use of NUMBRINO in patients with a recent or active history of myocardial infarction, coronary artery disease, congestive heart failure, irregular heart rhythm, abnormal ECG, uncontrolled hypertension, or thyrotoxicosis. 5.1 Potential for Abuse and Dependence Central nervous system (CNS) stimulants, including cocaine hydrochloride, have a high potential for abuse and dependence [see Drug Abuse and Dependence ( 9.2 , 9.3 )] . 5.2 Seizures It has been reported in the literature that cocaine hydrochloride may lower the convulsive threshold. The risk may be higher in patients with a history of seizures or in patients with prior electroencephalogram (EEG) abnormalities without seizures, but has been reported in patients with no prior history or EEG evidence of seizures. Monitor patients for development of seizures. 5.3 Blood Pressure and Heart Rate Increases As reported in the literature, cocaine hydrochloride causes an increase in observed blood pressure and heart rate. In the Phase 3 clinical studies with NUMBRINO, increases in blood pressure and heart rate were observed following pledget removal. Monitor for changes in vital signs, including heart rate and rhythm, after administration of NUMBRINO. Avoid use of NUMBRINO in patients with a history of myocardial infarction, coronary artery disease, congestive heart failure, irregular heart rhythm, abnormal ECG, or uncontrolled hypertension. Avoid use of additional vasoconstrictor agents such as epinephrine or phenylephrine with NUMBRINO. If concomitant use is unavoidable, prolonged vital sign and ECG monitoring may be required. Although not reported in the NUMBRINO clinical trials, myocardial infarction has been reported in the literature, and can occur when the drug has been used as recommended [see Adverse Reactions ( 6 )] . 5.4 Toxicology Screening The time after cocaine administration for which cocaine and its metabolites can be detected in plasma and urine depends on the sensitivity of the utilized assay method. The cocaine hydrochloride and its metabolites in NUMBRINO may be detected in plasma for up to one week after administration. Cocaine hydrochloride and its metabolites may be detected in urine toxicology screening for longer than one week after administration. 5.5 Known Hypersensitivity or Idiosyncrasy to the Sympathomimetic Amines NUMBRINO is contraindicated in patients with a known history of hypersensitivity to cocaine or to the components of the nasal solution. Cocaine is a sympathetic neuronal catecholamine reuptake inhibitor, which may potentiate the actions of concomitantly administered sympathomimetic amines. 5.6 Ophthalmic Use NUMBRINO is NOT FOR OPHTHALMIC USE. Cocaine can cause sloughing of the corneal epithelium and should not be used in the eyes. Pitting and ulceration of the cornea has been reported in the literature.
6 ADVERSE REACTIONS The following treatment-emergent adverse events are discussed in more detailed in other sections of the labeling: Increases in Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (> 1%) occurring in patients treated with NUMBRINO were hypertension, tachycardia, and sinus tachycardia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Omnivium Pharmaceuticals LLC at 1-888-807-1048 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. NUMBRINO nasal solution has been evaluated in one Phase 1 study, one QT study and two Phase 3 studies, which included 702 adult subjects who received a single application of NUMBRINO nasal solution 4%, NUMBRINO nasal solution 10%, or placebo. The randomized, double-blind, placebo controlled Phase 3 studies were conducted in adult patients undergoing diagnostic procedures and surgeries on or through the mucous membranes of the nasal cavities, of which 316 received NUMBRINO nasal solution 4%, 318 received NUMBRINO nasal solution 10%, and 168 received placebo. Safety was evaluated for up to 7 days after dosing. In a Phase 3 study, patients received a mean dose of 126 mg (80 to 160 mg, N=259) of cocaine hydrochloride using NUMBRINO nasal solution 4% and a mean dose of 319 mg (200 to 400 mg, N=259) of cocaine hydrochloride using NUMBRINO nasal solution 10% as a single application. The most common adverse reactions reported with NUMBRINO 4% are included in Table 1 (preexisting nasal conditions are not included). There were two patients treated with NUMBRINO nasal solution 4% who withdrew due to an adverse reaction. One patient developed anxiety and systolic hypertension and one patient developed intermittent paroxysmal tachycardia. Both patients developed symptoms within 10 minutes of nasal pledget application. Three patients treated with NUMBRINO nasal solution 10% required premature removal of pledgets due to nausea and diastolic hypertension; mild intermittent paroxysmal hypertension and paroxysmal tachycardia; and vasovagal syncope with bradycardia. Table 1. Common Adverse Reactions with NUMBRINO in > 1% of Treated Patients MedDRA System Organ Class and Preferred Term NUMBRINO, 4% (N=259) n, % NUMBRINO, 10% (N=259) n, % Placebo (N=128) n, % Vascular Disorders 203 (78) 224 (87) 86 (67) Hypertension 201 (78) 220 (85) 85 (66) Cardiac Disorders 31 (12) 47 (18) 10 (8) Tachycardia 12 (5) 28 (11) 1 (1) Bradycardia 8 (3) 1 (0.4) 5 (4) Sinus tachycardia 6 (2) 9 (4) 0 Investigations 13 (5) 30 (12) 8 (6) QRS prolonged 4 (2) 8 (3) 3 (2) QT interval prolonged 7 (3) 10 (4) 3 (2) 6.2 Postmarketing Experience The following adverse reactions have been identified during use of Cocaine Hydrochloride Nasal Solution. 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. Nervous system disorders: Headache, Seizure Cardiac disorders: Hypertension, tachycardia, atrial and ventricular arrhythmias, myocardial ischemia and infarction Psychiatric disorders: Anxiety