Included as part of the "PRECAUTIONS" Section
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, PATIENT INFORMATION].
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.
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].
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.
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]. 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].
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.
Effects On Ability To Drive And Operate Machinery
Treatment with PROVAYBLUE® may cause confusion, dizziness and disturbances in vision [see ADVERSE REACTIONS]. 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.
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a two-year carcinogenicity study, rats were administered oral doses of methylene blue at 5, 25, or 50 mg/kg. Methylene blue
caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year year carcinogenicity study, mice were
administered oral doses of methylene blue at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice.
Methylene blue was genotoxic in gene mutation assays in bacteria (Ames test), and in an in vitro sister chromatid exchange test and an in vitro chromosomal aberration test in Chinese hamster ovary (CHO) cells. Methylene blue was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with methylene blue.
Fertility studies with methylene blue have not been conducted. In vitro, methylene blue reduced motility of human sperm in a
concentration dependent manner.
Use In Specific Populations
PROVAYBLUE® may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a
methylene blue class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Methylene
blue produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32
and 16 times, respectively, the clinical dose of 1 mg/kg [see Data]. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized
pregnancies are 2-4% and 15-20%, respectively.
Fetal/neonatal adverse reactions
Intra-amniotic injection of a methylene blue class product hours to days prior to birth can result hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress and photosensitivity in the newborn. Following administration of PROVAYBLUE® to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care.
Methylene blue was administered orally to pregnant rats at doses of 50 to 350 mg/kg/day, during the period of organogenesis.
Maternal and embryofetal toxicities were observed at all doses of methylene blue, and were most evident at the 200 and 350
mg/kg/day doses. Maternal toxicity consisted of increased spleen weight. Embryo-fetal toxicities included reduced fetal weight, postimplantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m2) in rats is approximately 32 times a clinical dose of 1 mg/kg based on body surface area.
Methylene blue was administered orally to pregnant rabbits at doses of 50, 100, or 150 mg/kg/day, during the period of organogenesis. Maternal death was observed at the methylene blue dose of 100 mg/kg. Embryofetal toxicities included spontaneous abortion at all dose levels and a malformation (umbilical hernia) at the 100 and 150 mg/kg/day doses. The dose of 50 mg/kg (600 mg/m2) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area.
There is no information regarding the presence of methylene blue in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including genotoxicity discontinue breast-feeding during and for up to 8 days after treatment with PROVAYBLUE® [see CLINICAL PHARMACOLOGY].
The safety and effectiveness of PROVAYBLUE® have been established in pediatric patients. Use of PROVAYBLUE® is supported by two retrospective case series that included 2 pediatric patients treated with PROVAYBLUE® and 12 treated with another methylene blue class product. The case series included pediatric patients in the following age groups: 3 neonates (less than 1 month), 4 infants (1 month up to less than 2 years), 4 children (2 years up to less than 12 years), and 3 adolescents (12 years to less than 17 years). The efficacy outcomes were consistent across pediatric and adult patients in both case series [see Clinical Studies].
The retrospective case series included 3 patients age 65 years and over treated with PROVAYBLUE® (or a bioequivalent
formulation) and 5 treated with another methylene blue class product. The efficacy outcomes were consistent across adult and elderly patients in both case series [see Clinical Studies]. This drug is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, treatment of methemoglobinemia in these patients should use the lowest number of doses needed to achieve a response [see DOSAGE AND ADMINISTRATION].
Approximately 40% of methylene blue is excreted by the kidneys. Patients with any renal impairment should be monitored for
toxicities and potential drug interactions for an extended period of time following treatment with PROVAYBLUE®.
Methylene blue is extensively metabolized in the liver. Monitor patients with any hepatic impairment for toxicities and potential drug interactions for an extended period of time following treatment with PROVAYBLUE®.