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Procarbazine

Medically reviewed by Drugs.com. Last updated on Feb 12, 2019.

Pronunciation

See also: Adcetris

(proe KAR ba zeen)

Index Terms

  • Benzmethyzin
  • Ibenzmethyzin
  • MIH Hydrochloride
  • N-Methylhydrazine
  • PCB
  • PCZ
  • Procarbazine HCl
  • Procarbazine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Matulane: 50 mg

Matulane: 50 mg [contains corn starch, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow), methylparaben, propylparaben]

Brand Names: U.S.

  • Matulane

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent

Pharmacology

Procarbazine inhibits DNA, RNA, and protein synthesis by inhibiting transmethylation of methionine into transfer RNA; may also damage DNA directly through alkylation.

Absorption

Rapid and complete

Distribution

Crosses the blood-brain barrier and distributes into CSF

Metabolism

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

Excretion

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

Time to Peak

≤1 hour

Half-Life Elimination

~1 hour

Use: Labeled Indications

Hodgkin lymphoma: Treatment of stage III or IV Hodgkin lymphoma (in combination with other chemotherapy agents)

Off Label Uses

CNS tumors, anaplastic oligodendroglioma/oligoastrocytoma

Data (including long-term follow-up) from a multicenter, randomized, controlled phase III trial (EORTC 26951) in patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas supports the use of procarbazine (in combination with lomustine and vincristine [PCV regimen]) after radiotherapy for the treatment of this condition [van den Bent 2006], [van den Bent 2013]. Results from another clinical trial (RTOG 9402) demonstrated that the PCV regimen, followed by radiotherapy, significantly improved progression free survival compared to radiotherapy alone, although the difference in overall survival was not significant [Cairncross 2006]. However, long-term RTOG 9402 results illustrated that in a subset of patients with 1p/19q codeleted tumors, overall survival was significantly longer in patients who received PCV followed by radiotherapy compared to those who received radiotherapy alone [Cairncross 2013].

CNS tumors, low-grade gliomas

Long-term follow-up data from a randomized phase III study support the use of procarbazine (PCV regimen; in combination with lomustine, vincristine, and radiation therapy) for the treatment of low-grade gliomas in adults ≤40 years following resection and in adults ≥40 years [Buckner 2016].

Non-Hodgkin lymphomas, relapsed/refractory

Data from a study evaluating the use of CEPP (B) (cyclophosphamide, etoposide, procarbazine, and prednisone [with or without bleomycin]) in patients with recurrent or resistant non-Hodgkin lymphoma who are ineligible for hematopoietic stem cell transplantation or who cannot tolerate standard chemotherapy regimens supports the use of procarbazine (as a component of the 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 recurrent or refractory non-Hodgkin lymphoma [Coleman 2008].

Primary CNS lymphoma

Data from two multicenter phase II trials support the use of procarbazine (in combination with rituximab, high-dose methotrexate, leucovorin, and vincristine [R-MPV], followed by radiotherapy and cytarabine, and intrathecal methotrexate if indicated) for the treatment of newly diagnosed primary CNS lymphoma (PCNSL) [Morris 2013], [Shah 2007]. Data from a single center study also support the use of R-MPV, followed by consolidation high-dose chemotherapy and autologous stem cell transplant in newly diagnosed PCNSL [Omuro 2015]. Data from a multicenter, single-arm, phase II trial suggest that procarbazine (in combination with rituximab and high-dose methotrexate) may be an efficacious regimen in newly diagnosed PCNSL patients ≥65 years [Fritsch 2017].

Contraindications

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

Dosing: Adult

Note: Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016). 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.

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, begin within 4 weeks after radiotherapy) for 6 cycles (van den Bent 2006; van den Bent 2013) or 75 mg/m2 days 8 to 21 every 6 weeks (in combination with lomustine and vincristine, followed by radiotherapy) for up to 4 cycles (Cairncross 2006; Cairncross 2013).

CNS tumors (low-grade gliomas) (off-label use): PCV regimen: Oral: 60 mg/m2 days 8 to 21 every 8 weeks (after radiotherapy; in combination with lomustine and vincristine) for 6 cycles (Buckner 2016)

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)

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.

Non-Hodgkin lymphomas, relapsed/refractory (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)

Primary CNS lymphoma (off-label use): Oral:

R-MPV regimen: Induction: 100 mg/m2 for 7 days in cycles 1, 3, and 5 (in combination with rituximab, high-dose methotrexate, leucovorin, and vincristine; each cycle is 14 days), followed by reduced-dose whole brain radiotherapy and cytarabine (Morris 2013; Shah 2007) or autologous stem cell transplant (Omuro 2015). Two additional cycles of R-MPV may be administered to patients with partial response after initial induction chemotherapy; refer to protocols for details.

R-MP regimen: Patients ≥65 years: 60 mg/m2 on days 2 to 11 every 42 days (in combination with rituximab, high-dose methotrexate, and leucovorin) for 3 cycles, followed by maintenance treatment (beginning on day 43 after the last R-MP induction cycle): 100 mg once daily for 5 days every 28 days for 6 maintenance cycles; administer maintenance even if not all 3 induction cycles were completed (Fritsch 2017)

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

Note: Refer to individual protocols for specific dosage and interval information. Procarbazine is associated with a high emetic potential (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013). 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: Note: 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 (Kelly 2012). Manufacturer's labeling: Infants, Children, and Adolescents: Oral: 50 to 100 mg/m2/day once daily for 14 days of a 28-day cycle (Longo 1986)

BEACOPP regimen (high-risk): Limited data available: Children and Adolescents: 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 2 to 4 cycles (Kelly 2011)

CNS tumors; low-grade gliomas, WHO grades 1 and 2: Limited data available: TPCV regimen: Children <10 years: Oral: 50 mg/m2 every 6 hours for 4 doses (at hours 60, 66, 72, and 78) during a 42-day cycle (in combination with thioguanine, vincristine, and lomustine) for a total of 8 cycles (Ater 2012)

Dosing: Adjustment for Toxicity

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 (stomatitis, diarrhea), and hemorrhage or bleeding.

Dosing: Obesity

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.

Extemporaneously Prepared

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.

Administration

Oral: May be given as a single daily dose or in 2 to 3 divided doses. Some protocols administered in the evening; refer to specific protocol for details. Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2010).

Dietary Considerations

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

Storage

Protect from light.

Drug Interactions

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

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Benzhydrocodone: May enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: The use of benzhydrocodone is not recommended for patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation. Consider therapy modification

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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

Esketamine: May enhance the hypertensive effect of Monoamine Oxidase Inhibitors. 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

Iobenguane Radiopharmaceutical Products: Monoamine Oxidase Inhibitors may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. 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-Containing Products: 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

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

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

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

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

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

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

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

Adverse Reactions

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

ALERT: U.S. Boxed Warning

Experienced physician:

It is recommended that procarbazine 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.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Hematologic toxicity (leukopenia and thrombocytopenia) occurs 2 to 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 <4,000/mm3) or thrombocytopenia (platelets <100,000/mm3). Monitor for infections due to neutropenia.

• CNS toxicity: Withhold treatment for CNS toxicity (eg, paresthesias, neuropathies, confusion). CNS depression may occur; use with caution with other agents associated with CNS depression.

• Disulfiram-like reaction: Avoid ethanol consumption during procarbazine therapy, as a disulfiram-like reaction may occur.

• Gastrointestinal toxicities: Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016). May cause diarrhea and stomatitis; withhold treatment for diarrhea or stomatitis.

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

• Hemorrhage: Withhold treatment for hemorrhage or bleeding tendencies.

• Hypersensitivity: Generalized allergic reactions have been reported. Withhold treatment for hypersensitivity.

• Secondary malignancies: Procarbazine is possibly carcinogenic; acute myeloid leukemia and lung cancer have been reported following the use of procarbazine in combination with other chemotherapeutic agents.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment (toxicities may be increased).

• Renal impairment: Use with caution in patients with renal impairment (toxicities may be increased).

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: Procarbazine 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: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

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

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Procarbazine may cause fetal harm if administered to a pregnant female. There are case reports of fetal malformations in the offspring of pregnant women exposed to procarbazine as part of a combination chemotherapy regimen. Females of reproductive potential should avoid becoming pregnant during treatment. Azoospermia and infertility have been reported with procarbazine when used in combination with other chemotherapy agents.

Patient Education

• 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, sensitivity to light, 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 irritation, 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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