Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING PROVAYBLUE (methylene blue) injection, USP : is supplied in 10 mL and 2 mL single-dose ampules or single-dose vials. Each 10 mL ampule and vial contains 50 mg of methylene blue as a clear dark blue solution. Each 2 mL ampule and vial contains 10 mg of methylene blue as a clear dark blue solution. A box contains five ampules or vials. Box of 5 ampules of 50 mg/10 mL: NDC 0517-0374-05 Box of 5 ampules of 10 mg/2 mL: NDC 0517-0125-05 Box of 5 vials of 50 mg/10 mL: NDC 0517-0381-05 Box of 5 vials of 10 mg/2 mL: NDC 0517-0371-05 Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature] Any unused product or waste material should be disposed of in accordance with local practice. Do not refrigerate or freeze . Keep the ampule or the vial in the original package to protect from light.; Principal Display Panel - 50 mg/10 mL (5 mg/mL) Ampule Label NDC 0517 -0374- 01 Rx Only ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Ampule Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, INC. Shirley, NY 11967 Ampule Label 10 mL; Principal Display Panel - 50 mg/10 mL (5 mg/mL) Carton Label Rx only NDC 0517 -0374- 05 ProvayBlue ® (methylene blue) Injection USP 5 Single-Dose Ampules. Discard Unused Portion 50 mg/10 mL (5 mg/mL) (0.5%) Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM 10 mL Carton; Principal Display Panel - 10 mg/2 mL (5 mg/mL) Ampule Label NDC 0517 -0125- 01 Rx Only ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) Intravenous use only Use 5% Dextrose Injection When Diluting Single Dose Ampule Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, INC. Shirley, NY 11967 2 mL Ampule Label; Principal Display Panel - 10 mg/2 mL (5 mg/mL) Carton Label Rx only NDC 0517 -0125- 05 ProvayBlue ® (methylene blue) Injection USP 5 Single-Dose Ampules. Discard Unused Portion 10 mg/2 mL (5 mg/mL) (0.5%) Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM 2 mL Carton; Principal Display Panel - 50 mg/10 mL (5 mg/mL) Single-Dose Vial Label NDC 0517 -0381- 01 ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) Rx only Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Vial Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, Inc. Shirley, NY 11967 Single-Dose Vial Label 10 mL; Principal Display Panel - 50 mg/10 mL (5 mg/mL) Single-Dose Vial Carton Label NDC 0517 -0381- 05 ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) 5 Single-Dose Vials Discard Unused Portion Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM Single-Dose Vial Carton Label 10 mL; Principal Display Panel - 10 mg/2 mL (5 mg/mL) Single-Dose Vial Label NDC 0517 -0371- 01 ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) Rx only Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Vial. Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, Inc. Shirley, NY 11967 Single-Dose Vial Label 2 mL; Principal Display Panel - 10 mg/2 mL (5 mg/mL) Single-Dose Vial Carton Label Rx only NDC 0517 -0371- 05 ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) 5 Single-Dose Vials Discard Unused Portion Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM Single-Dose Vial Carton Label 2 mL
- 16 HOW SUPPLIED/STORAGE AND HANDLING PROVAYBLUE (methylene blue) injection, USP : is supplied in 10 mL and 2 mL single-dose ampules or single-dose vials. Each 10 mL ampule and vial contains 50 mg of methylene blue as a clear dark blue solution. Each 2 mL ampule and vial contains 10 mg of methylene blue as a clear dark blue solution. A box contains five ampules or vials. Box of 5 ampules of 50 mg/10 mL: NDC 0517-0374-05 Box of 5 ampules of 10 mg/2 mL: NDC 0517-0125-05 Box of 5 vials of 50 mg/10 mL: NDC 0517-0381-05 Box of 5 vials of 10 mg/2 mL: NDC 0517-0371-05 Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature] Any unused product or waste material should be disposed of in accordance with local practice. Do not refrigerate or freeze . Keep the ampule or the vial in the original package to protect from light.
- Principal Display Panel - 50 mg/10 mL (5 mg/mL) Ampule Label NDC 0517 -0374- 01 Rx Only ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Ampule Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, INC. Shirley, NY 11967 Ampule Label 10 mL
- Principal Display Panel - 50 mg/10 mL (5 mg/mL) Carton Label Rx only NDC 0517 -0374- 05 ProvayBlue ® (methylene blue) Injection USP 5 Single-Dose Ampules. Discard Unused Portion 50 mg/10 mL (5 mg/mL) (0.5%) Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM 10 mL Carton
- Principal Display Panel - 10 mg/2 mL (5 mg/mL) Ampule Label NDC 0517 -0125- 01 Rx Only ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) Intravenous use only Use 5% Dextrose Injection When Diluting Single Dose Ampule Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, INC. Shirley, NY 11967 2 mL Ampule Label
- Principal Display Panel - 10 mg/2 mL (5 mg/mL) Carton Label Rx only NDC 0517 -0125- 05 ProvayBlue ® (methylene blue) Injection USP 5 Single-Dose Ampules. Discard Unused Portion 10 mg/2 mL (5 mg/mL) (0.5%) Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM 2 mL Carton
- Principal Display Panel - 50 mg/10 mL (5 mg/mL) Single-Dose Vial Label NDC 0517 -0381- 01 ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) Rx only Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Vial Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, Inc. Shirley, NY 11967 Single-Dose Vial Label 10 mL
- Principal Display Panel - 50 mg/10 mL (5 mg/mL) Single-Dose Vial Carton Label NDC 0517 -0381- 05 ProvayBlue ® (methylene blue) Injection USP 50 mg/10 mL (5 mg/mL) (0.5%) 5 Single-Dose Vials Discard Unused Portion Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM Single-Dose Vial Carton Label 10 mL
- Principal Display Panel - 10 mg/2 mL (5 mg/mL) Single-Dose Vial Label NDC 0517 -0371- 01 ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) Rx only Intravenous use only Use 5% Dextrose Injection When Diluting Single-Dose Vial. Discard Unused Portion Manufactured by Cenexi for: Provepharm SAS Distributed by: American Regent, Inc. Shirley, NY 11967 Single-Dose Vial Label 2 mL
- Principal Display Panel - 10 mg/2 mL (5 mg/mL) Single-Dose Vial Carton Label Rx only NDC 0517 -0371- 05 ProvayBlue ® (methylene blue) Injection USP 10 mg/2 mL (5 mg/mL) (0.5%) 5 Single-Dose Vials Discard Unused Portion Intravenous use only For slow intravenous injection Use 5% Dextrose Injection When Diluting Distributed by: AMERICAN REGENT PROVEPHARM Single-Dose Vial Carton Label 2 mL
Overview
Methylene blue is an oxidation-reduction agent. Its chemical name is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride hydrate. The molecular formula of methylene blue is C 16 H 18 ClN 3 S.xH 2 O and its molecular weight of 319.86 g/mol for the anhydrous form. The structural formula of methylene blue is: PROVAYBLUE (methylene blue) injection USP is a sterile solution intended for intravenous administration. Each mL of solution contains 5 mg methylene blue and water for injection. PROVAYBLUE (methylene blue) injection, USP: is a clear dark blue solution with a pH value between 3.0 and 4.5. The osmolality is between 10 and 15 mOsm/kg. PROVAYBLUE (methylene blue) injection strength is expressed in terms of trihydrate. Figure
Indications & Usage
PROVAYBLUE is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. PROVAYBLUE (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.
Dosage & Administration
Administer 1 mg/kg intravenously over 5-30 minutes. ( 2.1 ) If methemoglobin level remains above 30% or if clinical symptoms persist, give a repeat dose of up to 1 mg/kg one hour after the first dose. ( 2.1 ) Administer a single dose of 1 mg/kg in patients with moderate or severe renal impairment. ( 2.2 ) 2.1 Dosage and Administration Ensure patent venous access prior to administration of PROVAYBLUE. Do not administer PROVAYBLUE subcutaneously. Administer PROVAYBLUE 1 mg/kg intravenously over 5-30 minutes. If the methemoglobin level remains greater than 30% or if clinical signs and symptoms persist, a repeat dose of PROVAYBLUE 1 mg/kg may be given one hour after the first dose. If methemoglobinemia does not resolve after 2 doses of PROVAYBLUE, consider initiating alternative interventions for treatment of methemoglobinemia. 2.2 Recommended Dosage for Renal Impairment The recommended dosage of PROVAYBLUE in patients with moderate or severe renal impairment (eGFR 15-59 mL/min/1.73 m 2 ) is a single dose of 1 mg/kg. If the methemoglobin level remains greater than 30% or if the clinical symptoms persist 1 hour after dosing, consider initiating alternative interventions for the treatment of methemoglobinemia. 2.3 Preparation PROVAYBLUE is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose Injection in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation. Avoid diluting with sodium chloride solutions, because it has been demonstrated that chloride reduces the solubility of methylene blue. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion.
Warnings & 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 saturation ( 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 and Opioids The development of serotonin syndrome has been reported with the 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 (MAOIs). Opioids and dextromethorphan may increase the risk of developing serotonin syndrome. 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 and opioids. 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.
Boxed Warning
SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS See full prescribing information for complete boxed warning. PROVAYBLUE may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of PROVAYBLUE with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids. ( 5.1 , 7.1 )
Contraindications
PROVAYBLUE is contraindicated in the following conditions: Severe hypersensitivity reactions to methylene blue or any other thiazine dye [see Warnings and Precautions ( 5.2 )] . Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia [see Warnings and Precautions ( 5.3 , 5.4 )]. PROVAYBLUE is contraindicated in the following conditions ( 4 ): Severe hypersensitivity to methylene blue Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia
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 (>2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent at 1-800-734-9236, 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 in adults with acquired methemoglobinemia was assessed in 31 patients who received at least 1 dose of PROVAYBLUE [see Clinical Studies ( 14 )] . Most doses administered were 1 mg/kg (82.9%), but doses from 0.78 mg/kg to 2 mg/kg were administered. All patients received at least one dose of PROVAYBLUE; two received two doses, and one received three doses. Serious adverse reactions occurred in 3.2% of patients who received PROVAYBLUE. A serious adverse reaction of seizure-like phenomenon was reported in one patient. Adverse reactions (≥2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena. The safety of PROVAYBLUE in pediatric patients with acquired methemoglobinemia was assessed in two retrospective case series that included two pediatric patients treated with PROVAYBLUE and 12 treated with another methylene blue product. The case series included patients in the following age groups: 3 neonates (<1 month), 4 infants (1 month to <2 years), 4 children (2 years to <12 years), and 3 adolescents (12 years to <17 years). The safety profile in pediatric patients was similar to that in adult patients. Other adverse reactions reported to occur following the administration of methylene blue class products include the following: Blood and lymphatic system disorders : hemolytic anemia, hemolysis, hyperbilirubinemia 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
Drug Interactions
Clinically significant drug interactions with PROVAYBLUE are described below: The concomitant use of PROVAYBLUE with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest PROVAYBLUE is a potent reversible inhibitor of monoamine oxidase. Avoid concomitant use of PROVAYBLUE with medicinal products that enhance serotonergic transmission including antidepressants like SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), MAOIs (monoamine oxidase inhibitors), bupropion, buspirone, clomipramine, mirtazapine, linezolid, opioids, and dextromethorphan because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. If the intravenous use of PROVAYBLUE cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe the patient closely for CNS effects for up to 4 hours after administration [see Warning and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )].
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