Prescription Drug Information: PROVAYBLUE (Page 2 of 3)

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.

12.2 Pharmacodynamics

Low concentrations of methylene blue speeds up the in vivo conversion of methemoglobin to hemoglobin. Methylene blue has been observed to stain tissues selectively. The exposure-response or –safety relationship for methylene is unknown.

Cardiac Electrophysiology

The results of a thorough QT study demonstrated PROVAYBLUE ® at an intravenous dose of 2 mg/kg as a 5-minute intravenous infusion had no effect on the QT, PR or QRS intervals.

12.3 Pharmacokinetics

The mean (CV%) Cmax and AUC of methylene blue 2,917 ng/mL (39%) and 13977 ng.hr/mL (21%) following a 2 mg/kg dose administered as a 5-minute intravenous infusion.

Distribution

The mean± standard deviation steady state volume of distribution of a 2 mg/kg dose of PROVAYBLUE ® was 255 L ± 58. The mean plasma protein binding of methylene blue is approximately 94% in vitro. Methylene blue exhibits concentration-dependent partitioning into blood cells in vitro. The blood-to-plasma ratio was 5.1±2.8 at 5 minutes from the start of a 2 mg/kg dose administered as a 5-minute intravenous infusion and reached a plateau of 0.6 at 4 hours in a clinical study. Methylene Blue is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro.

Elimination

Methylene blue has a half-life of approximately 24 hours in humans.

Metabolism

Methylene blue is metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9.

Azure B, which is a minor impurity in methylene blue, is also formed in humans as a metabolite of methylene blue, with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than methylene blue.

Excretion

Approximately 40% of methylene blue is excreted in to the urine unchanged.

Specific Populations

Renal Impairment


After a single 1 mg/kg dose of PROVAYBLUE, AUC0-96h increased by 52%, 116%, and 192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m2), moderate (eGFR 30-59 mL/min/1.73m2), and severe (eGFR 15-29 mL/min/1.732m2) renal impairment, respectively. Cmax increased by 42%, 34%, and 15% in subjects with mild, moderate, and severe renal impairment respectively [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)]. The half-life was unchanged in patients with mild to moderate renal impairment.


The AUC0-96h of Azure B after a single 1 mg/kg dose increased by 29%, 94%, and 339% in subjects with mild (estimated glomerular filtration rate (eGFR) 60 – 89 mL/min/1.73 m2), moderate (eGFR 30-59 mL/min/1.73m2), and severe (eGFR 15-29 mL/min/1.732m2) renal impairment, respectively. Cmax increased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairment respectively [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)]

Drug Interactions Studies

Clinical Studies:


The coadministration of 2 mg/kg dose of PROVAYBLUE® with midazolam (a CYP3A4 substrate), caffeine (a CYP1A2 substrate), warfarin (a CYP2C9 substrate), and dextromethorphan (a CYP2D6 substrate) in a cocktail study did not affect the exposure of these substrates compared to their exposure without PROVAYBLUE® administration.

In Vitro Studies:


Cytochrome P450 (CYP450) Enzymes:


Methylene blue inhibits CYP isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. Possible time-dependent inhibition of CYP2C9, CYP2D6 and CYP3A4/5 (testosterone as substrate) was also observed. Methylene blue induces CYP1A2 but does not induce CYP2B6 or CYP3A4.


UDP-Glucuronosyltransferase (UGT):


Methylene blue inhibits UGT1A9 and UGT1A4, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15.

Transporter:

Methylene blue is both a substrate for and an inhibitor of P-gp but is not a substrate for BCRP or OCT2 in vitro. Methylene blue is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3. Methylene blue inhibits OCT2, MATE1 and MATE2-K.

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