Methylene Blue

METHYLENE BLUE- methylene blue injection
Zydus Pharmaceuticals USA Inc.

BOXED WARNING

WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS AND OPIOIDS

Methylene blue may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. Avoid concomitant use of methylene blue with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and opioids [ see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

1 INDICATIONS AND USAGE

Methylene blue injection is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials [see Clinical Studies (14.1)].

Clinical Studies information is approved for PROVEPHARM SAS’s Provayblue® (Methylene blue solution, intravenous). However, due to PROVEPHARM SAS’s marketing exclusivity rights, this drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION

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 m2) 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.

3 DOSAGE FORMS AND STRENGTHS

Methylene blue injection, USP: 50 mg/10 mL (5 mg/mL) (0.5%) or 10 mg/2 mL (5 mg/mL) (0.5%) clear dark blue solution in single-dose vials.

4 CONTRAINDICATIONS

Methylene blue 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)].

5 WARNINGS AND PRECAUTIONS

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 methylene blue with serotonergic drugs and opioids.

Patients treated with methylene blue should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of methylene blue, 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 [see Drug Interactions (7), Patient Counseling Information (17)].

5.2 Hypersensitivity

Anaphylactic reactions to methylene blue class products have been reported. Patients treated with methylene blue should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of methylene blue and initiate supportive treatment. Methylene blue 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 methylene blue in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with methylene blue 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 [see Dosage and Administration (2.2)]. Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce methylene blue to its active form in vivo. Methylene blue 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. 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 [see Adverse Reactions (6.1)]. Use the lowest effective number of doses of methylene blue injection to treat methemoglobinemia. Discontinue methylene blue and consider alternative treatments of methemoglobinemia if severe hemolysis occurs. Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with methylene blue may result in severe hemolysis and severe anemia. Methylene blue 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 methylene blue 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 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 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 methylene blue have resolved.

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