Metoclopramide

CNS depressant with increased risk of CNS depression. Avoid concomitant use.

Dopaminergic agonist with opposing effects on dopamine. Avoid concomitant use due to decreased therapeutic effect and potential symptom exacerbation.

7 DRUG INTERACTIONS Concomitant use of antihypertensive medications and vasodilators: increased risk for hypotension, myocardial infarction, pneumonia, falls, and injuries ( 7.2 ) Dopamine antagonists such as neuroleptics or metoclopramide, may diminish the effectiveness of apomorphine hydrocloride ( 7.4 ) 7.1 5HT 3 Antagonists Based on reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron, the concomitant use of apomorphine hydrocloride with 5HT 3 antagonists including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated. 7.4 Dopamine Antagonists Since apomorphine hydrocloride is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of apomorphine hydrocloride.

Dopaminergic agonist with opposing effects on dopamine. Avoid concomitant use to prevent exacerbation of parkinsonian symptoms.

Cabergoline should not be administered concurrently with metoclopramide, a D2-antagonist that may antagonize cabergoline's dopaminergic effects.

7 DRUG INTERACTIONS Iron salts and dopamine D2 antagonists including metoclopramide: May reduce the effectiveness of carbidopa and levodopa extended-release capsules ( 7.2 , 7.3 ) 7.1 Monoamine Oxidase (MAO) Inhibitors The use of nonselective MAO inhibitors with carbidopa and levodopa extended-release capsules is contraindicated [see Contraindications ( 4 )] . 7.2 Dopamine D2 Receptor Antagonists and Isoniazid Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce the effectiveness of levodopa.

Dopaminergic agent with opposing effects on dopamine. Avoid concomitant use to prevent exacerbation of parkinsonian symptoms.

Increased risk of hypertension; concomitant use should be avoided.

Increased risk of hypertension. Avoid concomitant use.

Dopaminergic agonist with opposing effects on dopamine. Avoid concomitant use to prevent exacerbation of parkinsonian symptoms.

Concomitant use not recommended due to risk of additive extrapyramidal adverse reactions.

Risk of additive extrapyramidal adverse reactions. Concomitant use is not recommended.

Dopaminergic agonist with opposing effects on dopamine. Avoid concomitant use to prevent exacerbation of parkinsonian symptoms.

Dopaminergic agonist with opposing effects on dopamine. Avoid concomitant use to prevent exacerbation of parkinsonian symptoms.

CNS depressants with increased risk of CNS depression. Avoid concomitant use.

Product Clinical Comment on Concomitant Use [See Contraindications (4.1)] ; Predominant Effect/Risk [Hypertensive Reaction (HR) [See Warnings and Precautions (5.3)] ; or Serotonin Syndrome (SS) [See Warnings and Precautions (5.7)] ] Altretamine Use with caution If not otherwise specified in this table, consider avoiding concomitant use (see also information on medication-free intervals , use agent at the lowest appropriate dose, monitor for effects of the interaction, advise the patient to report potential effects, and be prepared to discontinue the agent and treat effects of the interaction Orthostatic hypotension [See Warnings and Precautions (5.5)] Buspirone Contraindicated HR Carbamazepine Contraindicated SS Chlorpromazine Use with caution Hypotensive effects Cyclobenzaprine Contraindicated SS Dextromethorphan Contraindicated SS; Psychosis, bizarre behavior Dopamine Contraindicated HR Droperidol Use with caution QT interval prolongation Entacapone Use with caution HR Fentanyl Use with caution SS Hydroxytryptophan Contraindicated SS Levodopa Contraindicated HR Lithium Use with caution SS Meperidine Contraindicated SS Methadone Use with caution SS Methyldopa Contraindicated HR Metoclopramide Use with caution HR/SS Mirtazapine Contraindicated SS Oxcarbazepine Use with caution because of close structural relationship with tricyclic antidepressants SS Rasagiline Contraindicated HR Reserpine Contraindicated HR S-adenosyl-L-methionine (SAM-e) Contraindicated SS Tapentadol Contraindicated HR/SS Tetrabenazine Contraindicated HR Tolcapone Use with caution HR Tramadol Use with caution SS; Increased seizure risk Tryptophan Contraindicated SS 7.2 Tyramine-Containing Foods and Beverages Tranylcypromine tablets inhibits intestinal MAO, which is responsible for the catabolism of tyramine in food and beverages.

e [See Warnings and Precautions (5.5)] ; f [See Warnings and Precautions (5.14)] ; g [See Overdosage (10.1)] Table 4: Clinically Significant Drug Interactions with Individual Products* Product Clinical Comment on Concomitant Use a Predominant Effect/Risk [Hypertensive Reaction (HR) b or Serotonin Syndrome (SS) c ] Altretamine Use with caution d Orthostatic hypotension e Buspirone Contraindicated a HR Carbamazepine Contraindicated a SS Chlorpromazine Use with caution d Hypotensive effects e Cyclobenzaprine Contraindicated a SS Dextromethorphan Contraindicated a SS; Psychosis, bizarre behavior Dopamine Contraindicated a HR Droperidol Use with caution d QT interval prolongation Entacapone Use with caution d HR Fentanyl Use with caution d SS Hydroxytryptophan Contraindicated a SS Levodopa Contraindicated a HR Lithium Use with caution d SS Meperidine Contraindicated a SS Methadone Use with caution d SS Methyldopa Contraindicated a HR Metoclopramide Use with caution d HR/SS Mirtazapine Contraindicated a SS Oxcarbazepine Use with caution d because of close structural relationship with tricyclic antidepressants SS Rasagiline Contraindicated a HR Reserpine Contraindicated a HR S-adenosyl-L-methionine (SAM-e) Contraindicated a SS Tapentadol Contraindicated a HR/SS Tetrabenazine Contraindicated a HR Tolcapone Use with caution d HR Tramadol Use with caution d SS; Increased seizure risk Tryptophan Contraindicated a SS * Some drugs in this table may also belong to groups listed in Table 3 above, and may be associated with additional interactions.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Monoamine Oxidase Inhibitors, Nonselective Beta-Adrenergic Antagonists, or Tricyclic Antidepressants: May produce severe, prolonged hypertension ( 7 ) Phenothiazines and Butyrophenones: May reduce or reverse the pressor effect of epinephrine ( 7 )

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Table 5: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, procaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate, Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Monoamine Oxidase Inhibitors, Nonselective Beta-adrenergic Antagonists, or Tricyclic Antidepressants : May produce severe, prolonged hypertension ( 7 ) Phenothiazines and butyrophenones : May reduce or reverse the pressor effect of epinephrine ( 7 )

Increased risk of methemoglobinemia when concurrently exposed to this oxidizing agent with local anesthetics.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Metoclopramide may diminish the effectiveness of bromocriptine, and bromocriptine may diminish metoclopramide's effectiveness. Concurrent use not recommended.

Increased risk of methemoglobinemia when local anesthetics are used concomitantly with metoclopramide.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., MARCAINE WITH EPINEPHRINE) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Strong CYP2D6 inhibitor that increases metoclopramide plasma concentrations and risk of extrapyramidal symptoms exacerbation. Dosage reduction recommended.

Increased risk of CNS depression. Avoid concomitant use and monitor for adverse reactions.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Strong CYP2D6 inhibitor that increases metoclopramide plasma concentrations and risk of extrapyramidal symptoms exacerbation. Dosage reduction recommended.

Metoclopramide alters gastric emptying, which may cause insulin to act before food leaves the stomach, leading to hypoglycemia. Insulin dosage or timing may require adjustment.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Increased risk of methemoglobinemia when used concurrently with lidocaine.

May cause methemoglobinemia when used concomitantly with lidocaine patch 5%.

Drug that increases risk of methemoglobinemia when used concurrently with lidocaine and capsaicin patch.

Increased risk of methemoglobinemia when concurrently exposed.

7.5 Drugs Associated with Methemoglobinemia Patients that are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following oxidizing agents: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea Antibiotics dapsone, sulfonamides, nitrofurantoin, para‑aminosalicylic acid Antimalarials chloroquine, primaquine Anticonvulsants phenytoin, sodium valproate, phenobarbital Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if lidocaine solutions containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.11) ] .

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.10) ] .

Increased risk of methemoglobinemia when local anesthetic is concurrently exposed to metoclopramide.

Concurrent exposure increases risk of methemoglobinemia in patients administered local anesthetics.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Increased risk of methemoglobinemia; drugs associated with methemoglobinemia when used with local anesthetics.

Increased risk of methemoglobinemia when used with lidocaine.

Increased risk of methemoglobinemia when lidocaine is concurrently exposed to metoclopramide.

Increased risk of methemoglobinemia when local anesthetics are concurrently exposed to oxidizing agents.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

Concurrent exposure increases risk of methemoglobinemia in patients administered mepivacaine.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Strong CYP2D6 inhibitor that increases metoclopramide plasma concentrations and risk of extrapyramidal symptoms exacerbation. Dosage reduction recommended.

Increased risk of methemoglobinemia when penicillin is concurrently administered with metoclopramide.

Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole The drug interactions with esomeprazole and metoclopramide do not apply to Noxafil tablets or Noxafil PowderMix ( 7.3 , 12.3 ). Avoid coadministration unless the benefit outweighs the risks ( 7.1 , 7.2 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.2 ) Digoxin Monitor digoxin plasma concentrations ( 7.2 ) Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections ( 7.1 ) 7.1 Effects of Other Drugs on Noxafil and Noxafil PowderMix Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Metoclopramide Mechanism and Clinical Effect(s) Concomitant use of Noxafil oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of Noxafil oral suspension.

Clinically Significant Drug Interactions Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine The administration of local anesthetic injections containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or phenothiazines may produce severe, prolonged hypotension or hypertension.

Clinically Significant Drug Interactions Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Concurrent administration of vasopressor drugs and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

Strong CYP2D6 inhibitor that increases metoclopramide plasma concentrations and risk of extrapyramidal symptoms exacerbation. Dosage reduction recommended.

Increased risk of developing methemoglobinemia when concurrently exposed to metoclopramide.

May enhance the neuromuscular blocking action of succinylcholine.

Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)].

Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.7 , 5.10 , 5.11 )] .

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

Increased risk of methemoglobinemia when used concurrently with triethanolamine salicylate.

Increased risk of methemoglobinemia when used with Trubrexa Transdermal Patch.

Metoclopramide may increase the rate and/or extent of absorption of acetaminophen from the small bowel.

Impair GI motility and decrease metoclopramide systemic absorption. Monitor for reduced therapeutic effect.

May reduce the bioavailability of atovaquone. Use only if other antiemetics are not available.

Metoclopramide may reduce bioavailability of atovaquone and should be used only if other antiemetics are not available.

May reduce the bioavailability of atovaquone. Administer concomitantly only if other antiemetics are not available.

Intravenous metoclopramide in combination with atropine reversed the delay in mexiletine absorption caused by atropine during pretreatment for anesthesia.

Intravenous metoclopramide in combination with atropine reversed the atropine-induced delay in mexiletine absorption during pretreatment for anesthesia.

Patients who are administered local anesthetics, including bupivacaine liposome injectable suspension, may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Bupivacaine Bupivacaine HCl administered together with bupivacaine liposome injectable suspension may impact the pharmacokinetic and/or physicochemical properties of bupivacaine liposome injectable suspension, and this effect is concentration dependent.

Increased risk of developing methemoglobinemia when concurrently exposed.

May adversely affect disease control through dopamine receptor antagonistic properties despite potentially increasing levodopa bioavailability.

May adversely affect disease control by dopamine receptor antagonistic properties, despite increasing gastric emptying and levodopa bioavailability.

Dopamine D2 receptor antagonist may reduce therapeutic effects of levodopa.

Metoclopramide may increase the rate and/or extent of absorption of cyclosporine from the small bowel.

Interaction may antagonize the effects of metoclopramide, a gastrointestinal motility drug.

Metoclopramide may diminish absorption of digoxin from the stomach.

Dopamine D2 receptor antagonist may reduce effectiveness of foslevodopa. Monitor for worsening Parkinson's symptoms.

Intervention Drugs with Decreased Absorption (e.g., digoxin, atovaquone, posaconazole oral suspension Interaction does not apply to posaconazole delayed-release tablets , fosfomycin) : Monitor for reduced therapeutic effect of the interacting drug.

Metoclopramide increases gastrointestinal motility and lowers serum concentration and urinary excretion of fosfomycin when co-administered.

Metoclopramide increases gastrointestinal motility and lowers serum concentration and urinary excretion of fosfomycin when coadministered.

Drug interactions may occur when hyoscyamine sulfate is used with metoclopramide.

7.3 Drugs That May Cause Methemoglobinemia When Used with PLIAGLIS Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

Narcotic analgesics antagonize the effects of metoclopramide on gastrointestinal motility.

Anticholinergic agents may antagonize the effects of prokinetic agents like metoclopramide. Monitor for reduced prokinetic efficacy.

Anticholinergic agents may antagonize the effects of prokinetic agents such as metoclopramide.

Dopamine antagonist may diminish the effectiveness of pramipexole dihydrochloride.

Weak/moderate CYP3A4/P-gp inhibitor that may increase sirolimus concentrations. Monitor and adjust dosage as needed.

Dopamine antagonist that may reduce the efficacy of ropinirole tablets.

May enhance the neuromuscular blocking action of succinylcholine.

Metoclopramide may increase the rate and/or extent of absorption of tetracycline from the small bowel.

Additive sedative effects can occur when metoclopramide is given with tranquilizers.

Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations.

In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.

In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.

Other The bioavailability of unbound fosinoprilat is not altered by coadministration of fosinopril with aspirin, chlorthalidone, cimetidine, digoxin, metoclopramide, nifedipine, propranolol, propantheline, or warfarin .

Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

( 7.1 , 7.2 ) 7.1 Effects of Other Drugs on Metoclopramide Table 3 displays the effects of other drugs on metoclopramide. Strong CYP2D6 Inhibitors, not Included in Antipsychotic Category Above Clinical Impact Increased plasma concentrations of metoclopramide; risk of exacerbation of extrapyramidal symptoms [see Clinical Pharmacology ( 12.3 )]. Intervention Reduce the Metoclopramide Orally Disintegrating Tablets dosage [ see Dosage and Administration ( 2.2 , 2.3 )] .

Interaction mentioned in table but clinical impact details not provided in excerpt.

palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

7.13 Gastrointestinal Motility Agents Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology ( 12.3 )] . No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.

Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics.

7.8 Dopaminergic Antagonists It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rasagiline.

7.8 Dopaminergic Antagonists It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rasagiline.

7.7 Dopaminergic Antagonists Dopamine antagonists, such as antipsychotics or metoclopramide, may decrease the effectiveness of XADAGO and exacerbate the symptoms of PD.

7.8 Dopaminergic Antagonists It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of ZELAPAR.