WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS PROVAYBLUE ® may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of PROVAYBLUE ® with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors ( 5.1 , 7.1 ). [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )] WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS See full prescribing information for complete boxed warning PROVAYBLUE ® may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use ( 5.1 , 7.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue PROVAYBLUE ® , treat the allergic reaction, and monitor until signs and symptoms resolve ( 5.2 ) Lack of Effectiveness: Consider alternative treatments if there is no resolution of methemoglobinemia after 2 doses ( 2.1 , 5.3 ) Hemolytic Anemia: Discontinue PROVAYBLUE ® and transfuse ( 5.4 ) Interference with In-Vivo Monitoring Devices: Use methods other than pulse oximetry to assess oxygen satruation ( 5.5 ) Effects on Ability to Drive and Operate Machinery: Advise patients to refrain from these activities until neurologic and visual symptoms have resolved ( 5.6 ) 5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs The development of serotonin syndrome has been reported with use of methylene blue class products. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors). Some of the reported cases were fatal. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Avoid concomitant use of PROVAYBLUE ® with serotonergic drugs. Patients treated with PROVAYBLUE ® should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of PROVAYBLUE ® , and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take serotonergic drugs within 72 hours after the last dose of PROVAYBLUE ® [see Drug Interactions ( 7 ), Patient Counseling Information ( 17 )] . 5.2 Hypersensitivity Anaphylactic reactions to methylene blue class products have been reported. Patients treated with PROVAYBLUE ® should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of PROVAYBLUE ® and initiate supportive treatment. PROVAYBLUE ® is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a methylene blue class product in the past. 5.3 Lack of Effectiveness Methemoglobinemia may not resolve or may rebound after response to treatment with PROVAYBLUE ® in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with PROVAYBLUE ® through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of PROVAYBLUE ® or if methemoglobinemia rebounds after a response, consider additional treatment options [see Dosage and Administration ( 2.2 )] . Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce PROVAYBLUE ® to its active form in vivo. PROVAYBLUE ® may not be effective in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. 5.4 Hemolytic Anemia Hemolysis can occur during treatment of methemoglobinemia with PROVAYBLUE ® . Laboratory testing may show Heinz bodies, elevated indirect bilirubin and low haptoglobin, but the Coombs test is negative. The onset of anemia may be delayed 1 or more days after treatment with PROVAYBLUE ® . The anemia may require red blood cell transfusions [see Adverse Reactions ( 6.1 )]. Use the lowest effective number of doses of PROVAYBLUE ® to treat methemoglobinemia. Discontinue PROVAYBLUE ® and consider alternative treatments of methemoglobinemia if severe hemolysis occurs. Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with PROVAYBLUE ® may result in severe hemolysis and severe anemia. PROVAYBLUE ® is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [see Contraindications ( 4 )]. 5.5 Interference with In Vivo Monitoring Devices Inaccurate Pulse Oximeter Readings The presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry. If a measure of oxygen saturation is required during or shortly after infusion of PROVAYBLUE ® , it is advisable to obtain an arterial blood sample for testing by an alternative method. Bispectral index monitor A fall in the Bispectral Index (BIS) has been reported following administration of methylene blue class products. If PROVAYBLUE ® is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed. 5.6 Effects on Ability to Drive and Operate Machinery Treatment with PROVAYBLUE ® may cause confusion, dizziness and disturbances in vision [see Adverse Reactions ( 6 )] . Advise patients to refrain from driving or engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery until such adverse reactions to PROVAYBLUE ® have resolved. 5.7 Interference with Laboratory Tests PROVAYBLUE ® is a blue dye which passes freely into the urine and may interfere with the interpretation of any urine test which relies on a blue indicator, such as the dipstick test for leucocyte esterase.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions ( 5.1 )] Anaphylaxis [see Warnings and Precautions ( 5.2 )] Lack of Effectiveness [see Warnings and Precautions ( 5.3 )] Hemolytic Anemia [see Warnings and Precautions ( 5.4 )] Interference with In-Vivo Monitoring Devices [see Warnings and Precautions ( 5.5 )] Effects on Ability to Drive and Operate Machinery [see Warnings and Precautions ( 5.6 )] Interference with Laboratory Tests [see Warnings and Precautions ( 5.7 )] The most commonly reported adverse reactions (≥10%) are pain in extremity, chromaturia, dysgeusia, feeling hot, dizziness, hyperhidrosis, nausea, skin, discoloration and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent at 1-800-734-9236 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 safety of PROVAYBLUE ® was determined in 82 healthy adults of median age of 36 years (range, 19-55 years); 54% were male, and 68% were white. Each individual in the safety population received a single dose of PROVAYBLUE ® 2 mg/kg intravenously. There was one serious adverse reaction reported (syncope due to sinus pauses of 3-14 seconds). The most common (≥2%) moderate or severe adverse reactions were pain in the extremity (56%), headache (7%), feeling hot (6%), syncope (4%), back pain (2%), hyperhidrosis (2%) and nausea (2%). Table 1 lists the adverse reactions of any severity that occurred in at least 2% of individuals who received PROVAYBLUE ® . Table 1. Adverse Reactions Following Infusion of PROVAYBLUE ® 2 mg/kg Adverse Reaction Any Grade TEAE (n=82) Moderate- Severe TEAE (n=82) Pain in extremity 69 84% 46 56% Chromaturia 61 74% 0 Dysgeusia 16 20% 1 1% Feeling hot 14 17% 5 6% Dizziness 13 16% 4 5% Hyperhidrosis 11 13% 2 2% Nausea 11 13% 2 2% Skin discoloration 11 13% 0 Headache 8 10% 6 7% Musculoskeletal pain 7 9% 0 Paresthesia oral 7 9% 0 Paresthesia 7 9% 0 Infusion site pain 5 6% 1 1% Feeling cold 5 6% 0 Pallor 4 5% 0 Dermatitis contact 4 5% 0 Syncope 3 4% 3 4% Influenza like illness 3 4% 1 1% Pruritus 3 4% 1 1% Anxiety 3 4% 0 Decreased appetite 3 4% 0 Chest discomfort 3 4% 0 Back pain 2 2% 2 2% Cold sweat 2 2% 1 1% Dizziness postural 2 2% 1 1% Muscle spasms 2 2% 1 1% Presyncope 2 2% 1 1% Vomiting 2 2% 1 1% Arthralgia 2 2% 1 1% Chills 2 2% 0 Diarrhea 2 2% 0 Discomfort 2 2% 0 Dyspnea 2 2% 0 Erythema 2 2% 0 Hypoesthesia oral 2 2% 0 Infusion site discomfort 2 2% 0 Limb discomfort 2 2% 0 Oral discomfort 2 2% 0 Catheter site pain 2 2% 0 Ecchymosis 2 2% 0 Other adverse reactions reported to occur following administration of methylene blue class products include the following: Blood and lymphatic system disorders : hemolytic anemia, hemolysis, hyperbilirubinemia, methemoglobinemia Cardiac disorders : palpitations, tachycardia Eye disorders : eye pruritus, ocular hyperemia, vision blurred Gastrointestinal disorders : abdominal pain lower, dry mouth, flatulence, glossodynia, tongue eruption General disorders and administration site conditions : death, infusion site extravasation, infusion site induration, infusion site pruritus, infusion site swelling, infusion site urticaria, peripheral swelling, thirst Investigations : elevated liver enzymes Musculoskeletal and connective tissue disorders : myalgia Renal and urinary disorders : dysuria Respiratory, thoracic and mediastinal disorders : nasal congestion, oropharyngeal pain, rhinorrhea, sneezing Skin and subcutaneous tissue disorders : necrotic ulcer, papule, phototoxicity Vascular disorders : hypertension