PROVAYBLUE (Page 3 of 5)

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

Avoid concomitant use of PROVAYBLUE® with medicinal products that enhance serotonergic transmission including SSRIs (selective serotonin reuptake inhibitors), MAO inhibitors, bupropion, buspirone, clomipramine, mirtazapine and venlafaxine; because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. Although the mechanism is not clearly understood, literature reports suggest inhibition of MAO by methylene blue may be involved. If the intravenous use of PROVAYBLUE® cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe closely the patient for CNS effects for up to 4 hours after administration [see Warning and Precautions ( 5.1) and Clinical Pharmacology ( 12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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.

Clinical Considerations

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.

Data

Animal Data

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, post-implantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m 2) 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/m 2) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area.

8.2 Lactation

Risk Summary

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 ( 12.3)] .

8.4 Pediatric Use

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 ( 14)].

8.5 Geriatric Use

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 ( 14)] . 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 ( 2)] .

8.6 Renal Impairment

Methylene blue concentrations increased in subjects with renal impairment (eGFR 15 to 89 mL/min/1.73m2) significantly [see Clinical Pharmacology ( 12.3)]. Adjust PROVAYBLUE® dosage in patients with moderate or severe renal impairment (eGFR 15 to 59 mL/min/1.73 m2) [see Dosage and Administration ( 2.2)]. No dose adjustment is recommended in patients with mild renal impairment (eGFR 60 – 89 mL/min/1.73 m2)

8.7 Hepatic Impairment

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 ®.

10 OVERDOSAGE

Hypotension, wheezing and reduced oxygenation have been reported in patients who received methylene blue class products in single doses of 3 mg/kg or more.

Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a methylene blue class product caused nausea, vomiting, precordial pain, dyspnea, tachypnea, chest tightness, tachycardia, apprehension, tremor, mydriasis, blue staining of the urine, the skin and mucous membranes, abdominal pain, dizziness, paresthesia, headache, confusion, mild methemoglobinemia (up to 7%) and electrocardiogram changes (T-wave flattening or inversion) These effects lasted 2-12 hours following administration.

A severe overdosage (single dose of 20 mg/kg or more) of a methylene blue class product caused severe intravascular hemolysis, hyperbilirubinemia and death.

In case of overdose of PROVAYBLUE ® , maintain the patient under observation until signs and symptoms have resolved, monitor for cardiopulmonary, hematologic and neurologic toxicities, and institute supportive measures as necessary.

11 DESCRIPTION

PROVAYBLUE ® is an oxidation-reduction agent. PROVAYBLUE ® (methylene blue) is a sterile solution intended for intravenous administration. Each PROVAYBLUE ® , 10 mL ampule contains 50 mg Proveblue ® methylene blue and water for injection q.s. Each PROVAYBLUE ® 2 mL ampule contains 10 mg Proveblue ® methylene blue and water for injection q.s. Each mL of solution contains 5 mg methylene blue and water for injection q.s.

Methylene blue is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride. The molecular formula of methylene blue is C 16 H 18 ClN 3 S and its molecular weight is 319.86 g/mol. Its structural formula is:

Figure

PROVAYBLUE™ 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylene blue is a water soluble thiazine dye that promotes a non-enzymatic redox conversion of metHb to hemoglobin. In situ, methylene blue is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin.

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