METHYLENE BLUE: 846 Adverse Event Reports & Safety Profile

Methylene blue, USP 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, USP is: Methylene blue injection, USP is a sterile solution intended for intravenous administration. Each mL of solution contains 5 mg methylene blue USP and water for injection USP. Additionally, it contains the excipients sodium citrate dihydrate USP and citric acid anhydrous USP in single dose glass vial. 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. Methylene blue injection, USP strength is expressed in terms of trihydrate. Image

1.

Indications And Usage

Methylene blue injection is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. Methylene blue injection (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. ( 1 )

AND 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 methylene blue injection. Do not administer methylene blue injection subcutaneously. Administer methylene blue injection 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 methylene blue injection 1 mg/kg may be given one hour after the first dose. If methemoglobinemia does not resolve after 2 doses of methylene blue injection, consider initiating alternative interventions for treatment of methemoglobinemia.

2.2 Recommended Dosage for Renal Impairment The recommended dosage of methylene blue injection 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 Methylene blue injection 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.

2.4 Instructions for Use of prefilled syringe Remove the Pre-filled Syringe from the carton Inspect visually for particulate matter and discoloration prior to administration. Do not use the solution if it contains particulate matter.

Figure

1 3. Hold the syringe upright on the Luer Lock part/luer cover of the syringe barrel. With the other hand, take hold of the cap/closure and gently turn anti-clockwise as shown in the figure 2.

Figure

2 4.Do not touch the syringe tip or the working surface to keep it sterile. 5. Connect the syringe to an appropriate injection connection depending on the route of administration. 6. Expel air bubble(s). Adjust the dose (if applicable). 7. Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. 8. Discard unused portion. image description image description

CONTRAINDICATIONS : Methylene blue can cause fetal harm when administered to a pregnant woman. An association exists between the use of methylene blue in amniocentesis and atresia of the ileum and jejunum, ileal occlusions, and other adverse effects in the neonate. (2, 3) Methylene blue is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Intraspinal and subcutaneous injections are contraindicated. Methylene blue is contraindicated in patients with a known hypersensitivity to the drug.

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 (≥2%) included headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chengdu Shuode Pharmaceutical Co., Ltd at +86-288-782-7168, 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 methylene blue injection in adults with acquired methemoglobinemia was assessed in 24 patients who received at least 1 dose of methylene blue injection <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Most doses administered were 1 mg/kg (88.5%), but doses from 1 mg/kg to 2 mg/kg were administered. All patients received at least one dose of methylene blue injection; two received two doses. Serious adverse reactions occurred in 4.2% of patients who received methylene blue injection. 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 methylene blue injection in pediatric patients with acquired methemoglobinemia was assessed in two retrospective case series that included two pediatric patients treated with methylene blue injection and 12 treated with another methylene blue product. The case series included patients in the following age groups: 3 neonates (&lt;1 month), 4 infants (1 month to &lt;2 years), 4 children (2 years to &lt;12 years), and 3 adolescents (12 years to &lt;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

AND PRECAUTIONS Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue methylene blue injection, 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 methylene blue injection 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 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 methylene blue injection with serotonergic drugs and opioids. Patients treated with methylene blue injection should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of methylene blue injection, 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 methylene blue injection <span class="opacity-50 text-xs">[see Drug Interactions (7) and Patient Counseling Information (17) ]</span> .

5.2 Hypersensitivity Anaphylactic reactions to methylene blue injection class products have been reported. Patients treated with methylene blue injection should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of methylene blue injection and initiate supportive treatment. Methylene blue injection is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a methylene blue injection class product in the past.

5.3 Lack of Effectiveness Methemoglobinemia may not resolve or may rebound after response to treatment with methylene blue injection in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with methylene blue injection through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of methylene blue injection or if methemoglobinemia rebounds after a response, consider additional treatment options <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce methylene blue injection to its active form in vivo . Methylene blue injection 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 methylene blue injection. 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 methylene blue injection. The anemia may require red blood cell transfusions <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Use the lowest effective number of doses of methylene blue injection to treat methemoglobinemia. Discontinue methylene blue injection and consider alternative treatments of methemoglobinemia if severe hemolysis occurs. Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with methylene blue injection may result in severe hemolysis and severe anemia. Methylene blue injection is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 methylene blue injection, 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 methylene blue injection 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 methylene blue injection may cause confusion, dizziness and disturbances in vision <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . 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 methylene blue injection have resolved.

5.7 Interference with Laboratory Tests Methylene blue injection 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.

PRECAUTIONS : Drug Interactions: Methylene blue may interact with any drug that acts as a serotonin reuptake inhibitor (SRI) including, amongst others, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans and ergot alkaloids; such combinations may have the consequence of potentially fatal serotonin toxicity (serotonin syndrome). Methylene blue should not be co- administered with any drug that acts as an SRI. Pregnancy: Pregnancy Category X: Epidemiologic evidence exists that methylene blue is a teratogen. An association exists between the use of methylene blue in amniocentesis and atresia of the ileum and jejunum, ileal occlusions, and other adverse effects in the neonate. (2,3) Methylene blue injection should not be administered to pregnant women during amniocentesis due to the risk of teratogenicity and other newborn adverse effects (see CONTRAINDICATIONS ). Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD Deficiency): Methylene blue should be avoided in patients with G6PD deficiency due to the risk of paradoxical methemoglobinemia and hemolysis. (5,6)

Renal

Failure: Methylene blue should be used with caution in patients with severe renal impairment (see CLINICAL PHARMACOLOGY ). Methylene blue must be injected intravenously very slowly over a period of several minutes to prevent local high concentration of the compound from producing additional methemoglobin. Do not exceed recommended dosage. Large intravenous doses of methylene blue produce nausea, abdominal and precordial pain, dizziness, headache, profuse sweating, mental confusion, and the formation of methemoglobin.

7.

Drug Interactions

Clinically significant drug interactions with methylene blue injection are described below: The concomitant use of methylene blue injection with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest methylene blue injection is a potent reversible inhibitor of monoamine oxidase. Avoid concomitant use of methylene blue injection 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 methylene blue injection 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 )] .

Pure Deionizer Water