Rapid and complete

Crosses the blood-brain barrier and distributes into CSF, liver, kidney, intestine, and skin

Oxidized to active metabolites methylazoxy-procarbazine and benzylazoxy-procarbazine, then further metabolized to inactive metabolites (Kintzel 1995)

Urine (70% as inactive metabolites [Kintzel 1995]; <5% as unchanged drug)

≤1 hour

~1 hour

Treatment of Hodgkin lymphoma

Data from a multicenter, randomized, controlled phase III trial in patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas supports the use of procarbazine (PCV regimen) after radiotherapy for the treatment of this condition [Van den Bent 2006]. Another clinical trial demonstrated that early treatment with procarbazine (PCV regimen) followed by radiotherapy does not prolong survival and is associated with significant toxicity; however, tumors lacking 1p and 19q alleles may be more responsive [Cairncross 2006].

Data from a study evaluating the use of CEPP (B) (cyclophosphamide, etoposide, procarbazine, and prednisone [with or with out bleomycin]) in patients with non-Hodgkin lymphoma supports the use of procarbazine (CEPP regimen) for the treatment of this condition [Chao 1990].

Data from a study evaluating the use of PEP-C (prednisone, etoposide, procarbazine, cyclophosphamide) regimen in patients with recurrent non-Hodgkin lymphoma supports the use of procarbazine (PEP-C regimen) for the treatment of this condition [Coleman 2008].

Data from a multicenter trial in patients with newly diagnosed primary CNS lymphoma (PCNSL) supports the use of procarbazine in the treatment of patients with this condition [Deangelis 2002].

Hypersensitivity to procarbazine or any component of the formulation; inadequate bone marrow reserve

Note: Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Roila, 2010). The manufacturer suggests that an estimated lean body mass be used in obese patients and patients with rapid weight gain due to edema, ascites, or abnormal fluid retention.

Hodgkin lymphoma:

MOPP regimen: While procarbazine is approved as part of the MOPP regimen, the MOPP regimen is generally no longer used due to improved toxicity profiles with other combination regimens used in the treatment of Hodgkin lymphoma.

BEACOPP, standard or escalated regimen (off-label dosing): Oral: 100 mg/m2 days 1 to 7 every 21 days (in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone) for 8 cycles (Diehl, 2003)

Non-Hodgkin lymphomas (NHL; off-label use):

CEPP regimen: Oral: 60 mg/m2 days 1 to 10 every 28 days (in combination with cyclophosphamide, etoposide and prednisone) (Chao, 1990)

PEP-C regimen: Oral: 50 mg daily at bedtime (length of induction cycle depends on phase of treatment and blood counts; frequency may vary based on tolerance in maintenance cycle; in combination with prednisone, etoposide, and cyclophosphamide) (Coleman, 2008)

CNS tumors, anaplastic oligodendroglioma/oligoastrocytoma (off-label use): PCV regimen: Oral: 60 mg/m2 days 8 to 21 every 6 weeks (in combination with lomustine and vincristine) for 6 cycles (van den Bent, 2006) or 75 mg/m2 days 8-21 every 6 weeks (in combination with lomustine and vincristine) for up to 4 cycles (Cairncross, 2006).

Primary CNS lymphoma (off-label use): Oral: 100 mg/m2 for 7 days in cycles 1, 3, and 5 (in combination with methotrexate [high-dose], vincristine, methotrexate [intrathecal], leucovorin, dexamethasone, cytarabine [high-dose], and whole brain radiation) (DeAngelis, 2002).

Refer to adult dosing; use with caution.

Note: Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011). The manufacturer suggests that an estimated lean body mass be used in obese patients and patients with rapid weight gain due to edema, ascites, or abnormal fluid retention.

Hodgkin lymphoma:

MOPP regimen: While procarbazine is approved as part of the MOPP regimen, the MOPP regimen is generally no longer used due to improved toxicity profiles with other combination regimens used in the treatment of Hodgkin lymphoma.

BEACOPP regimen (off-label dosing): Oral: 100 mg/m2 days 0 to 6 of a 21-day treatment cycle (in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone) for 4 cycles (Kelley, 2011).

No dosage adjustment provided in manufacturer’s labeling; use with caution; may result in increased toxicity. However, because predominantly inactive metabolites are excreted via the kidneys, dosage adjustment is not necessary (Kintzel, 1995).

No dosage adjustment provided in manufacturer’s labeling; use with caution; may result in increased toxicity. The following adjustments have been reported in literature:

Floyd, 2006:

Transaminases 1.6-6 times ULN: Administer 75% of dose

Transaminases >6 times ULN: Use clinical judgment

Serum bilirubin >5 mg/dL or transaminases >3 times ULN: Avoid use

King, 2001: Serum bilirubin >5 mg/dL or transaminases >180 units/L: Avoid use

Withhold treatment (promptly) for any of the following: CNS toxicity (eg, paresthesia, confusion, neuropathy), hematologic toxicity (WBC <4000/mm3 or platelets <100,000/mm3), hypersensitivity, gastrointestinal toxicities (stomatisis, diarrhea), and hemorrhage or bleeding.

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012). Note: The manufacturer suggests that an estimated lean body mass be used in obese patients and patients with rapid weight gain due to edema, ascites, or abnormal fluid retention.

A 10 mg/mL oral suspension may be prepared using capsules, glycerin, and strawberry syrup. Empty the contents of ten 50 mg capsules into a mortar. Add 2 mL glycerin and mix to a thick uniform paste. Add 10 mL strawberry syrup in incremental proportions; mix until uniform. Transfer the mixture to an amber glass bottle and rinse mortar with small amounts of strawberry syrup; add rinses to the bottle in sufficient quantity to make 50 mL. Label “shake well” and “protect from light”. Stable for 7 days at room temperature.

Matulane® data on file, Sigma Tau Pharmaceuticals, Inc.

Oral: May be given as a single daily dose or in 2 to 3 divided doses. Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011; Roila, 2010).

Avoid tyramine-containing foods/beverages. Some examples include aged or matured cheese, air-dried or cured meats (including sausages and salamis), fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce and other soybean condiments.

Protect from light.

Alpha-/Beta-Agonists (Indirect-Acting): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Avoid combination

Alpha1-Agonists: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details.Avoid combination

Altretamine: May enhance the orthostatic hypotensive effect of Monoamine Oxidase Inhibitors. Monitor therapy

Amphetamines: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Amphetamines. While linezolid and tedizolid may interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details.Avoid combination

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Apraclonidine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Apraclonidine. Monoamine Oxidase Inhibitors may increase the serum concentration of Apraclonidine. Avoid combination

AtoMOXetine: Monoamine Oxidase Inhibitors may enhance the neurotoxic (central) effect of AtoMOXetine. Avoid combination

Atropine (Ophthalmic): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Atropine (Ophthalmic). Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Avoid combination

Beta2-Agonists: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Betahistine: Monoamine Oxidase Inhibitors may increase the serum concentration of Betahistine.Monitor therapy

Bezafibrate: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid combination

Blood Glucose Lowering Agents: Monoamine Oxidase Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Brimonidine (Ophthalmic): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Brimonidine (Ophthalmic). Monoamine Oxidase Inhibitors may increase the serum concentration of Brimonidine (Ophthalmic). Monitor therapy

Brimonidine (Topical): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Brimonidine (Topical). Monoamine Oxidase Inhibitors may increase the serum concentration of Brimonidine (Topical). Monitor therapy

Buprenorphine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

BuPROPion: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of BuPROPion. Avoid combination

BusPIRone: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Specifically, blood pressure elevations been reported. Avoid combination

CarBAMazepine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Management: Avoid concurrent use of carbamazepine during, or within 14 days of discontinuing, treatment with a monoamine oxidase inhibitor. Avoid combination

Carbocisteine: Procarbazine may enhance the adverse/toxic effect of Carbocisteine. Specifically, procarbazine may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Monitor therapy

Cerebrolysin: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors.Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Codeine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Codeine. Monitor therapy

COMT Inhibitors: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Consider therapy modification

Cyclobenzaprine: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Cyproheptadine: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Cyproheptadine. Cyproheptadine may diminish the serotonergic effect of Monoamine Oxidase Inhibitors. Avoid combination

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Deutetrabenazine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Deutetrabenazine. Avoid combination

Dexmethylphenidate: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Dexmethylphenidate. Avoid combination

Dextromethorphan: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Avoid combination

Diethylpropion: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Diethylpropion.Avoid combination

Dihydrocodeine: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monitor therapy

Diphenoxylate: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Domperidone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Domperidone. Monoamine Oxidase Inhibitors may diminish the therapeutic effect of Domperidone. Domperidone may diminish the therapeutic effect of Monoamine Oxidase Inhibitors. Monitor therapy

DOPamine: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of DOPamine. Management: Initiate dopamine at no greater than one-tenth (1/10) of the usual dose in patients who are taking (or have taken within the last 2 to 3 weeks) monoamine oxidase inhibitors. Monitor for an exaggerated hypertensive response to dopamine. Consider therapy modification

Doxapram: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Doxapram. Monitor therapy

Droxidopa: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Droxidopa. Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

EPINEPHrine (Nasal): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of EPINEPHrine (Nasal). Monitor therapy

EPINEPHrine (Oral Inhalation): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Avoid combination

Epinephrine (Racemic): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy

EPINEPHrine (Systemic): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of EPINEPHrine (Systemic). Monitor therapy

FentaNYL: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Guanethidine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Heroin: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Heroin. Avoid combination

HYDROcodone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

HYDROmorphone: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of HYDROmorphone. Avoid combination

Indoramin: Monoamine Oxidase Inhibitors may enhance the hypotensive effect of Indoramin. Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Isometheptene: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Isometheptene.Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Levodopa: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Of particular concern is the development of hypertensive reactions when levodopa is used with nonselective MAOI. Management: The concomitant use of nonselective monoamine oxidase inhibitors (MAOIs) and levodopa is contraindicated. Discontinue the nonselective MAOI at least two weeks prior to initiating levodopa. Monitor patients taking a selective MAOIs and levodopa. Consider therapy modification

Levonordefrin: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Levonordefrin.Avoid combination

Levosulpiride: Benzamide Derivatives may enhance the adverse/toxic effect of Levosulpiride. Monitor therapy

Linezolid: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Linezolid. Avoid combination

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lithium: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Lithium. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Maprotiline: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Meperidine: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Avoid combination

Meptazinol: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Meptazinol. Avoid combination

Mequitazine: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Mequitazine.Avoid combination

Metaraminol: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Metaraminol.Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methadone: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monitor therapy

Methyldopa: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Methyldopa.Avoid combination

Methylene Blue: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Methylphenidate. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome.Monitor therapy

Mianserin: Monoamine Oxidase Inhibitors may enhance the neurotoxic effect of Mianserin. Avoid combination

Mirtazapine: Monoamine Oxidase Inhibitors may enhance the neurotoxic (central) effect of Mirtazapine. While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Moclobemide: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Moclobemide.Avoid combination

Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of other Monoamine Oxidase Inhibitors. Monoamine Oxidase Inhibitors may enhance the serotonergic effect of other Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Morphine (Liposomal): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Morphine (Liposomal). Avoid combination

Morphine (Systemic): Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Morphine (Systemic). Avoid combination

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nefopam: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Nefopam. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Norepinephrine: Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Norepinephrine. Monitor therapy

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Opioid Analgesics: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

OxyCODONE: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: Seek alternatives when possible. Avoid use of oxycodone/naltrexone during and within 14 days after monoamine oxidase inhibitor treatment. Non-US labeling for some oxycodone products states that such use is contraindicated. Consider therapy modification

OxyMORphone: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.Consider therapy modification

Pheniramine: May enhance the anticholinergic effect of Monoamine Oxidase Inhibitors. Avoid combination

Pholcodine: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pindolol: Monoamine Oxidase Inhibitors may enhance the hypotensive effect of Pindolol. Management: Canadian labeling for pindolol states that concurrent use with a monoamine oxidase inhibitor is not recommended. Consider therapy modification

Pizotifen: Monoamine Oxidase Inhibitors may enhance the anticholinergic effect of Pizotifen. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Reboxetine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Reboxetine. Avoid combination

Reserpine: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Reserpine. Existing MAOI therapy can result in paradoxical effects of added reserpine (e.g., excitation, hypertension). Management: Monoamine oxidase inhibitors (MAOIs) should be avoided or used with great caution in patients who are also receiving reserpine. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details.Avoid combination

Serotonin 5-HT1D Receptor Agonists: Monoamine Oxidase Inhibitors may decrease the metabolism of Serotonin 5-HT1D Receptor Agonists. Management: If MAO inhibitor therapy is required, naratriptan, eletriptan or frovatriptan may be a suitable 5-HT1D agonist to employ. Exceptions: Eletriptan; Frovatriptan; Naratriptan. Avoid combination

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Serotonin Reuptake Inhibitor/Antagonists: Monoamine Oxidase Inhibitors may enhance the adverse/toxic effect of Serotonin Reuptake Inhibitor/Antagonists. While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Serotonin/Norepinephrine Reuptake Inhibitors: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

SUFentanil: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Specifically, the risk for serotonin syndrome or opioid toxicities (eg, respiratory depression, coma) may be increased. Management: Sufentanil should not be used with monoamine oxidase (MAO) inhibitors (or within 14 days of stopping an MAO inhibitor) due to the potential for serotonin syndrome and/or excessive CNS depression. Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tapentadol: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Specifically, the additive effects of norepinephrine may lead to adverse cardiovascular effects. Tapentadol may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome.Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tetrabenazine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Tetrahydrozoline (Nasal): Monoamine Oxidase Inhibitors may enhance the hypertensive effect of Tetrahydrozoline (Nasal). Avoid combination

Tianeptine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Tricyclic Antidepressants: Monoamine Oxidase Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Avoid combination

Tryptophan: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Valbenazine: May enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Frequency not always defined.

Cardiovascular: Edema, flushing, hypotension, syncope, tachycardia

Central nervous system: Apprehension, ataxia, chills, coma, confusion, depression, dizziness, drowsiness, falling, fatigue, hallucination, headache, hyporeflexia, insomnia, lethargy, nervousness, neuropathy, nightmares, pain, paresthesia, seizure, slurred speech, unsteadiness

Dermatologic: Alopecia, dermatitis, diaphoresis, hyperpigmentation, pruritus, skin rash, urticaria

Endocrine & metabolic: Gynecomastia (in prepubertal and early pubertal males)

Gastrointestinal: Nausea and vomiting (60% to 90%; increasing the dose in a stepwise fashion over several days may minimize), abdominal pain, anorexia, constipation, diarrhea, dysphagia, hematemesis, melena, stomatitis, xerostomia

Genitourinary: Reduced fertility (>10%), azoospermia (reported with combination chemotherapy), hematuria, nocturia

Hematologic & oncologic: Malignant neoplasm (2% to 15%; secondary; nonlymphoid; reported with combination therapy), anemia, bone marrow depression, eosinophilia, hemolysis (in patients with G6PD deficiency), hemolytic anemia, pancytopenia, petechia, purpura, thrombocytopenia

Hepatic: Hepatic insufficiency, jaundice

Hypersensitivity: Hypersensitivity reaction

Infection: Herpes virus infection, increased susceptibility to infection

Neuromuscular & skeletal: Arthralgia, foot-drop, myalgia, tremor, weakness

Ophthalmic: Accommodation disturbance, diplopia, nystagmus, papilledema, photophobia, retinal hemorrhage

Otic: Hearing loss

Renal: Polyuria

Respiratory: Cough, epistaxis, hemoptysis, hoarseness, pleural effusion, pneumonitis, pulmonary toxicity (<1%)

Miscellaneous: Fever

Experienced physician:

It is recommended that procarbazine hydrochloride be given only by or under the supervision of a physician experienced in the use of potent antineoplastic drugs. Adequate clinical and laboratory facilities should be available to patients for proper monitoring of treatment.

Concerns related to adverse effects:

• Bone marrow suppression: Hematologic toxicity (leukopenia and thrombocytopenia) may occur 2-8 weeks after treatment initiation. Allow ≥1 month interval between radiation therapy or myelosuppressive chemotherapy and initiation of procarbazine treatment. Withhold treatment for leukopenia (WBC <4000/mm3) or thrombocytopenia (platelets <100,000/mm3). Monitor for infections due to neutropenia.

• CNS toxicity: Withhold treatment for CNS toxicity.

• Disulfiram-like reaction: Avoid ethanol consumption, may cause disulfiram-like reaction.

• Gastrointestinal toxicities: Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011; Roila, 2010). May cause diarrhea and stomatitis; withhold treatment for diarrhea or stomatitis.

• Hemolysis: May cause hemolysis and/or presence of Heinz inclusion bodies in erythrocytes.

• Hemorrhage: Withhold treatment for hemorrhage.

• Hypersensitivity: Withhold treatment for hypersensitivity.

• Infertility: Azoospermia and infertility have been reported with procarbazine when used in combination with other chemotherapy agents.

• Secondary malignancies: Possibly carcinogenic; acute myeloid leukemia and lung cancer have been reported following use.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• MAO inhibitor activity: Possesses MAO inhibitor activity and has potential for severe drug and food interactions; follow MAOI diet (avoid tyramine-containing foods).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

CBC with differential, platelet and reticulocyte count, urinalysis, liver function test, renal function test. Monitor for infections, CNS toxicity, and gastrointestinal toxicities.

D

Adverse events were observed in animal reproduction studies. There are case reports of fetal malformations in the offspring of pregnant women exposed to procarbazine as part of a combination chemotherapy regimen. Women of reproductive potential should avoid becoming pregnant during treatment.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, nausea, vomiting, lack of appetite, dry mouth, hair loss, abdominal pain, constipation, headache, muscle pain, joint pain, skin discoloration, flushing, or insomnia. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), shortness of breath, severe dizziness, passing out, tachycardia, edema, confusion, difficulty focusing, mouth irritation, mouth sores, polyuria, sweating a lot, slurred speech, enlarged breasts (males), diarrhea, burning or numbness feeling, vision changes, eye pain, severe eye irritation, nightmares, hearing loss, tremors, seizures, change in balance, severe loss of strength and energy, mouth sores, difficulty swallowing, involuntary eye movements, mood changes, or hallucinations (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.