PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Principal Display Panel Text for Container Label:. NDC 17478-504-10Methylene BlueInjection1% (10 mg/mL)For slow Intravenous administration.10 mL Single-dose VialRx only Akorn Logo. Figure.

BOXED WARNING SECTION.


WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS. Methylene Blue Injection may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of Methylene Blue Injection with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (see WARNINGS and PRECAUTIONS, Drug Interactions).

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY:. Methylene blue will produce two opposite actions on hemoglobin. Low concentrations will convert methemoglobin to hemoglobin. High concentrations convert the ferrous iron of reduced hemoglobin to ferric iron which results in the formation of methemoglobin.Methylene blue is metabolized in the body to leukomethylene blue which is excreted primarily in the urine. Some unchanged drug is also excreted in the urine. (1).

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS:. Methylene blue can cause fetal harm when administered to 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 known hypersensitivity to the drug.

DESCRIPTION SECTION.


DESCRIPTION:. Methylene Blue Injection is sterile solution of Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-, chloride, trihydrate. Each mL contains methylene blue, 10 mg in water for injection q.s. pH adjusted with hydrochloric acid and/or sodium hydroxide when necessary.The structural formula is:The molecular formula is:C16H18ClN3S 3H2O MW 373.90. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION:. 0.1 to 0.2 mL per kg body weight (0.045 to 0.09 mL per pound body weight). Inject methylene blue intravenously very slowly over period of several minutes.Methylene blue must be injected intravenously very slowly over period of several minutes to prevent local high concentration of the compound from producing additional methemoglobin. Do not exceed recommended dosage.Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.

DRUG INTERACTIONS SECTION.


Drug Interactions: Methylene blue may interact with any drug that acts as 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.

HOW SUPPLIED SECTION.


HOW SUPPLIED:. Methylene Blue Injection, 1% is supplied as follows:NDC 17478-504-011 mL in cc (partially filled) vials in packages of 10.NDC 17478-504-1010 mL vials in packages of 10.The vials are packaged with Flip Tear-Off Seal. The seal can either be flipped normally to reveal the rubber stopper or be totally removed so the rubber stopper can be taken out of the vial. The plastic button is attached to the metal seal, which when pulled, tears the seal at the score line allowing the metal portion to be removed.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE:. Drug-induced methemoglobinemia.

PRECAUTIONS SECTION.


PRECAUTIONS:. Drug Interactions: Methylene blue may interact with any drug that acts as 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 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 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.

PREGNULLNCY SECTION.


Pregnancy: Pregnancy Category X: Epidemiologic evidence exists that methylene blue is 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 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.

REFERENCES SECTION.


REFERENCES:. DiSanto AR, Wagner JG. Pharmacokinetics of highly ionized drugs II: methylene blue absorption, metabolism, and excretion in man and dog after oral administration. Pharm Sci. 1972; 61:1086-1090.Cragan JD. Teratogen update: methylene blue. Teratology. 1999; 60:42-48.Kidd SA, Lancaster PA, Anderson JC, Boogert A, Fisher CC, Robertson R, et al. Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat Diagn. 1996; 16:39-47.Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase (MAOA) confirms theoretical prediction. Br Pharmacol. 2007; 152:946-51.Beutler E. G6PD Deficiency. Blood. 1994; 84:3613-3636.Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Popliski H, Shimonov J, Beig S, Berkovitch M. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010; 33:713-726.Methylene Blue and Methylene Blue Injection were in compliance with USP 39, but differs from the Current USP 40 with respect to active assay, Impurities: Azure A, Azure B, Azure C, and unknown impurities. AKORNManufactured by: Akorn, Inc. Lake Forest, IL 60045MB00N Rev. 11/17. DiSanto AR, Wagner JG. Pharmacokinetics of highly ionized drugs II: methylene blue absorption, metabolism, and excretion in man and dog after oral administration. Pharm Sci. 1972; 61:1086-1090.. Cragan JD. Teratogen update: methylene blue. Teratology. 1999; 60:42-48.. Kidd SA, Lancaster PA, Anderson JC, Boogert A, Fisher CC, Robertson R, et al. Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat Diagn. 1996; 16:39-47.. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase (MAOA) confirms theoretical prediction. Br Pharmacol. 2007; 152:946-51.. Beutler E. G6PD Deficiency. Blood. 1994; 84:3613-3636.. Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Popliski H, Shimonov J, Beig S, Berkovitch M. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010; 33:713-726.

SPL UNCLASSIFIED SECTION.


(FOR SLOW INTRAVENOUS ADMINISTRATION)Rx only.

STORAGE AND HANDLING SECTION.


STORAGE:. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Flip Tear-Off Seal: Directions for Use:With the thumb, flip the plastic button up to reveal the rubber stopper.Pull the button to tear the seal at the score line and twist to remove.. With the thumb, flip the plastic button up to reveal the rubber stopper.. Pull the button to tear the seal at the score line and twist to remove.

WARNINGS SECTION.


WARNINGS:. Methylene blue should not be given by subcutaneous or intrathecal injection.. Methylene blue is potent monoamine oxidase inhibitor: Methylene blue has been demonstrated to be potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). (4) (See DRUG INTERACTIONS.) Serotonin toxicity is characterized by development of neuromuscular hyperactivity (tremor, clonus, myoclonus and hyperreflexia, and, in the advanced stage, pyramidal rigidity); autonomic hyperactivity (diaphoresis, fever, tachycardia, tachypnoea, and mydriasis); and altered mental status (agitation, exctextent, and in the advanced stage, confusion). If methylene blue is judged to be indicated, SRIs must be ceased, prior to treatment/procedure/surgery.