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简介：   Natulan®（Procarbazinum）-对霍奇金病，多发性骨髓瘤、肺癌等多种癌症治疗有一定效果 作用与用途 本品具有细胞毒作用，在体内释放出甲基正离子与DNA结合，使其解聚。 临床用于治疗何杰金氏病，恶性淋巴瘤，骨髓瘤，黑色素瘤，脑瘤，肺癌。 剂量与用法 口服，从每日50mg〜100mg/m 2开始，1周后逐渐增加，至每日150mg〜200mg/m 2为止，一般分3次服，连用2〜3周，然后停药2周再用， 或用维持量每日100mg / m 2，至毒性出现时停药。 Fachinformation des Arzneimittel-Kompendium der Schweiz® Natulan® Sigma-Tau Pharma AG AMZV Zusammensetzung Wirkstoff: Procarbazinum ut Procarbazini hydrochloridum Hilfsstoffe: Excipiens pro capsula Galenische Form und Wirkstoffmenge pro Einheit Hartkapseln zu 50 mg Indikationen/Anwendungsmöglichkeiten Zur Kombinationschemotherapie bei Morbus Hodgkin Zur Kombinationschemotherapie bei Non-Hodgkin Lymphomen Dosierung/Anwendung Procarbazin soll unter Aufsicht von in der Chemotherapie erfahrenen Onkologen/Hämatologen angewendet werden. Procarbazin wird in einer täglichen Dosis von 100 bis 150 mg / m2 Körperoberfläche als Einmalgabe an 5 bis 14 Tagen eines monatlichen Behandlungszyklus in Kombination mit anderen Zytostatika verabreicht, wobei die Dosierung und Dauer der Behandlung: a)dem verwendeten Chemotherapie-Protokoll b)dem aktuellen Funktionszustand des Knochenmarks (Verlaufskontrolle von Granulozyten und Thrombozyten im peripheren Blut) c)der Knochenmarkreserve (kumulative chemotherapeutische Vorbehandlung, vorange-gangene Strahlentherapie) und d)der zu erwartenden myelosuppressiven Wirkung im Rahmen der Kombinations-chemotherapie mit anderen Zytostatika anzupassen ist. Spezielle Dosierungsanweisungen Bei Patienten mit Nieren- oder Leberinsuffizienz liegen keine klinischen Studien vor. Bei schwerer Nieren- oder Leberinsuffizienz ist Natulan kontraindiziert. Bei leichter bis mässiggradiger Nieren- oder Leberinsuffizienz können keine Dosierungsempfehlungen gemacht werden. Bei Kindern und Jugendlichen gelten die gleichen Dosierungsempfehlungen wie für Erwachsene. Einnahme mit/unabhängig von Mahlzeit. Die Kapseln sind mit Wasser ganz zu schlucken ohne zu kauen oder zu lutschen. Sie sollten nicht geöffnet werden. Bei der Handhabung sollten möglichst Einmalhandschuhe verwendet werden respektive unmittelbar nach dem Kontakt mit den Kapseln sollten die Hände gewaschen werden. Es ist darauf zu achten, dass das in den Kapseln enthaltene Pulver (z.B. bei einer Beschädigung der Kapsel) nicht eingeatmet wird und nicht mit der Haut oder Schleimhaut in Kontakt kommt. Falls es zu einem Hautkontakt kommt, ist die Stelle mit Wasser und Seife zu waschen, bei Augenkontakt ist mit Wasser zu spülen. Beschädigte Kapseln dürfen nicht eingenommen werden, sondern sollten fachgerecht entsorgt werden. Wird Pulver aus der Kapsel verschüttet, soll dieses mit einem feuchten Wegwerf-Tuch aufgenommen und in einem verschlossenen Behältnis fachgerecht entsorgt werden. Kontraindikationen Überempfindlichkeit gegenüber Procarbazin oder einem der Hilfsstoffe. Myelosuppression mit Granulozyto- und Thrombozytopenie, die nicht auf eine Knochenmarkinfiltration durch die maligne Grunderkrankung zurückzuführen ist. Schwangerschaft und Stillzeit. Schwere Niereninsuffizienz, schwere Leberinsuffizienz. Warnhinweise und Vorsichtsmassnahmen Aufgrund der myelosuppressiven Eigenschaften von Procarbazin sind vor und während der Verabreichung der Substanz regelmässige Blutbildkontrollen, einschliesslich der Bestimmung der Thrombozytenzahl sowie der Granulozytenzahl durch Untersuchung des Differentialblutbildes, durchzuführen. Aufgrund der vorwiegend renalen Elimination ist die Nierenfunktion (Serum-Kreatinin, Kreatinin-Clearance) vor und während der Verabreichung von Procarbazin laborchemisch zu bestimmen. Ebenfalls ist die Leberfunktion wegen der hepatischen Metabolisierung von Procarbazin laborchemisch zu bestimmen. Ein Unterbruch der Behandlung mit einer Procarbazin enthaltenden Kombinationschemotherapie sollte erwogen werden bei: -Leukopenie (Leukozyten <4'000/mm3) -Thrombozytopenie (Thrombozyten <100'000 /mm3) -Blutungen oder Blutungstendenz -Symptome wie Parästhesien, Neuropathien oder Verwirrtheit -Überempfindlichkeitsreaktion -Abdominellen Krämpfen oder Diarrhöe -Symptomen einer Stomatitis -pulmonalen Veränderungen im Sinne einer interstitiellen Pneumoni Vor Beginn der Behandlung müssen männliche Patienten über das Risiko der Sterilität aufgeklärt werden. Aufgrund der immunosuppressiven Eigenschaften sollte eine Prophylaxe mit Lebendvakzinen (wie Gelbfieber) nicht während der Behandlung durchgeführt werden. Interaktionen Die gleichzeitige Einnahme von Procarbazin und Alkohol kann infolge Hemmung der Aldehyddehydrogenase ein Antabus-Syndrom (wie Disulfiram) auslösen. Während der Behandlung mit Natulan sind deshalb alkoholische Getränke zu vermeiden. Da Procarbazin ein schwacher Hemmer der Monoaminoxidase (MAO) ist, kann die gleichzeitige Einnahme von Procarbazin und Nahrungsmitteln mit einem hohen Gehalt an Tyramin zu Bluthochdruckkrisen führen. Daher müssen Käse, Streichkäse, Bier, Rotwein, Wermut, Sherry, Portwein, Hartwurst (Salami), Leber, Hefe oder Hefe-Extrakte, Bohnen, überreife Früchte, Avocado, Bananen, Feigen, Hering, geräuchertes oder mariniertes Fleisch oder Fisch, vermieden werden. Aufgrund der MAO-Hemmung sind auch Wechselwirkungen mit sympathomimetisch wirksamen Arzneimitteln (Antiasthmatika, abschwellende Nasentropfen/-sprays, Antihypotonika), trizyklischen Antidepressiva (z.B. Amitriptylin, Imipramin) und Serotonin-Wiederaufnahme-Inhibitoren (z.B. Sertralin) möglich. Die Wirkung von Barbituraten, Antihistaminika, Phenothiazinen, Narkotika und hypotensiv wirkenden Arzneimitteln kann verstärkt werden. Die gleichzeitige Verabreichung von Procarbazin mit oralen Antidiabetika und Insulin kann deren blutzuckersenkenden Effekt verstärken. Procarbazin ist ein Prodrug. An seinem Metabolismus sind CYP450 Isoenzyme, vorrangig CYP3A4, beteiligt. Interaktionsstudien mit CYP3A4-Inhibitoren (wie Ketoconazol) oder CYP3A-Induktoren (wie Rifampicin) wurden nicht durchgeführt. Bei deren Anwendung in Kombination mit Natulan ist daher Vorsicht geboten. Allopurinol kann zu einer Verlängerung der Procarbazin-Wirkung führen. Schwangerschaft/Stillzeit Procarbazin besitzt mutagene, erbgutschädigende Eigenschaften. Im Tierversuch ist Procarbazin embryotoxisch und teratogen. Procarbazin ist generell während der Schwangerschaft kontraindiziert. Bei vitaler Indikation zur Behandlung einer schwangeren Patientin soll jedoch eine medizinische Beratung über das mit der Behandlung verbundene Risiko von schädigenden Wirkungen für das Kind erfolgen. Frauen im gebärfähigen Alter sollen nicht schwanger werden und während der Behandlung mit Procarbazin wirksame Methoden zur Empfängnisverhütung anwenden. Tritt während der Behandlung dennoch eine Schwangerschaft ein, so ist die Möglichkeit einer genetischen Beratung zu nutzen. Männern, die mit Procarbazin behandelt werden, wird empfohlen, während der Behandlung und bis 6 Monate danach kein Kind zu zeugen und sich vor Therapiebeginn wegen der Möglichkeit einer irreversiblen Infertilität nach Therapie mit Procarbazin über eine Sperma-Konservierung beraten zu lassen. Zum Übertritt von Procarbazin oder seiner Metaboliten in die Muttermilch liegen keine Daten vor. Während der Behandlung ist das Stillen kontraindiziert. Ist aus therapeutischen  Gründen eine Anwendung von Natulan in der Stillzeit notwendig, so muss abgestillt werden. Wirkung auf die Fahrtüchtigkeit und auf das Bedienen von Maschinen Da Natulan Nausea und Erbrechen verursachen kann, kann Procarbazin einen Einfluss auf die Fahrtüchtigkeit oder die Fähigkeit Maschinen zu bedienen haben. Unerwünschte Wirkungen Die sehr häufig auftretende dosisbegrenzende akute Toxizität von Procarbazin manifestiert sich als reversible Myelosuppression mit Granulozytopenie und Thrombozytopenie, die etwa eine Woche nach Therapiebeginn auftritt und bis zwei Wochen nach Therapieende persistieren kann. Infektionen Häufig: Infektionen, Herpes zoster. Selten: Sepsis. Neoplasmen Sekundäre Malignome, akute myeloische Leukämie (AML)( 0,5-15,5%), myelodysplastisches Syndrom (0,9-23%), Myelosklerose, Non-Hodgkin-Lymphom (1,5%) Lungenkarzinom nach einer Latenzzeit von 3-5 Jahren. Blut- und Lymphsystem Sehr häufig: Knochenmarksuppression, Anämie, Neutropenie, Leukopenie. Häufig: Thrombozytopenie mit Blutungstendenz, Panzytopenie. Sehr selten: Hämolytische Anämie. Immunsystem Häufig: allergische Reaktion mit Hypereosinophilie oder Fieber. Selten: Angioödem. Sehr selten: anaphylaktischer Schock. Psychiatrische Störungen Häufig: Verwirrtheit. Selten: Depression. Sehr selten: Halluzinationen, Psychosen. Nervensystem Häufig: Neuropathien, Parästhesien der Extremitäten, Schläfrigkeit. Selten: Kopfschmerzen. Sehr selten: Krampanfälle, Ruhelosigkeit. Atmungsorgane Häufig: Interstitielle Pneumonie. Sehr selten: Lungenfibrose. Gastrointestinale Störungen Sehr häufig: Nausea, Erbrechen. Häufig: Anorexie, Obstipation, Diarrhöe, Stomatitis. Selten: abdominale Schmerzen. Leber und Galle Häufig: Leberfunktionsstörungen. Selten: Hepatitis, Ikterus. Haut Häufig: makulopapuläres Exhantem, Hautrötung, Urtikaria, Alopezie. Sehr selten: toxische epidermale Nekrolyse (Lyell Syndrom), Erythema exsudativum multiforme (Stevens-Johnson-Syndrom). Muskelskelettsystem Sehr selten: Myalgien, Knorpel- und Knochennekrosen. Reproduktionssystem und Brust Sehr häufig: Azoospermie (90%), Sterilität (50%), beides irreversibel. Bei Frauen, die nach Kombinationschemotherapie mit Procarbazin eine normale Ovarialfunktion wiedererlangten, wurde bislang keine Beeinträchtigung der Fertilität oder eine Zunahme der Zahl von Fehlgeburten oder Fehlbildungen beschrieben. Überdosierung Die Überdosierung von Procarbazin kann insbesondere bei Patienten mit eingeschränkter Knochenmarkreserve zu einer schweren Hypo- oder Aplasie des Knochenmarks führen.  In diesem Fall können der Symptomatik entsprechende supportive Behandlungsmassnahmen auf einer internistisch-onkologischen Intensivstation notwendig sein, wie z.B. antibiotische Behandlung und Thrombozytenersatz. In jedem Fall sind bei Überdosierung regelmässige Blutbildkontrollen notwendig. Es gibt kein Antidot für Procarbazin. Eigenschaften/Wirkungen ATC-Code: L01XB01 Wirkungsmechanismus/Pharmakodynamik Procarbazin, ein Phenylhydrazinderivat, ist ein Prodrug. Zytostatisch wirken die durch Oxidation der Hydrazingruppe entstehenden Oxazogruppen über Alkylierung der DNS. Beschrieben ist weiterhin die Bildung von Methylradikalen, welche über Methylierung der t-RNS zur Hemmung der Proteinsynthese führen. Zusätzlich ist Procarbazin ein schwacher Inhibitor der Monoaminooxidase (MAO). Pharmakokinetik Absorption Nach oraler Applikation von Procarbazin wird die maximale Konzentration im Plasma nach etwa 60 Min. erreicht. Die Bioverfügbarkeit ist hoch. Zum Einfluss von Nahrung auf die Absorption liegen keine Daten vor. Distribution Zur Plasmaproteinbindung von Procarbazin und zum Verteilungsvolumen liegen keine Daten vor. Procarbazin passiert die Bluthirnschranke. Metabolismus Procarbazin wird extensiv metabolisiert. Der erste Schritt, die Bildung einer Azo-Verbindung durch Oxidation der Hydrazingruppe, erfolgt sowohl enzymatisch via Cytochrom P450 in der Leber und Niere als auch spontan in Gegenwart von molekularem Sauerstoff. Die weitere Metabolisierung, die hauptsächlich in Leber und Niere stattfindet, führt zu verschiedenen, teilweise aktiven Verbindungen (siehe «Eigenschaften/Wirkungen»). Elimination Procarbazin wird in Form von Metaboliten eliminiert, zu 70% über die Nieren, zu 4-12% mit den Faeces und ein Teil wird in Form von CO2 und Methan abgeatmet. Die Halbwertzeit von Procarbazin beträgt 10 Minuten (i.v.-Gabe), diejenige der Azo-Verbindung 3 Stunden. Kinetik spezielle Patientengruppen Daten zur Pharmakokinetik bei Patienten mit Leber- oder Niereninsuffizienz, bei älteren Patienten, Kindern und Jugendlichen liegen nicht vor. Präklinische Daten Tierexperimentelle Untersuchungen mit Procarbazin zur Fertilität, Embryotoxizität und Teratogenität ergaben bei verschiedenen Tierspezies Hinweise auf ein embryotoxisches und teratogenes Potential sowie auf eine Beeinträchtigung der Fertilität. Bei den Nachkommen behandelter weiblicher Ratten erwies sich Procarbazin als transplazentares neurotropes Kanzerogen. Procarbazin erwies sich in verschiedenen Tests zur Mutagenität in vitro und in vivo als mutagener Wirkstoff. Eine krebserzeugende Wirkung ist für Procarbazin tierexperimentell in verschiedenen Spezies nachgewiesen. Sonstige Hinweise Haltbarkeit Das Arzneimittel darf nur bis zu dem auf dem Behälter mit «EXP» bezeichneten Datum verwendet werden. Besondere Lagerungshinweise Bei Raumtemperatur (15–25 °C) in der Originalpackung vor Licht und Feuchtigkeit geschützt und ausser Reichweite von Kindern lagern. Hinweise für die Handhabung Bei der Handhabung von Natulan und der Entsorgung sind die Richtlinien für Zytostatika zu befolgen (siehe auch «Dosierung/Anwendung»). Zulassungsnummer 58'474 (Swissmedic) Zulassungsinhaberin sigma-tau Pharma AG, Zofingen Stand der Information Dezember 2013 Packungen Publiziert am 31.10.2014 V2016-10-24

Pronunciation

(proe KAR ba zeen)

Index TermsBenzmethyzinIbenzmethyzinN-MethylhydrazinePCBPCZProcarbazine HClProcarbazine HydrochlorideDosage Forms

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

Capsule, Oral, as hydrochloride:

Matulane: 50 mg

Brand Names: U.S.MatulanePharmacologic CategoryAntineoplastic Agent, Alkylating AgentPharmacology

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, liver, kidney, intestine, and skin

Metabolism

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

Treatment of Hodgkin lymphoma

Off Label UsesCNS tumors, anaplastic oligodendroglioma/oligoastrocytoma

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].

Non-Hodgkin lymphomas

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].

Primary CNS lymphoma

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].

Contraindications

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 (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).

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Pediatric

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).

Dosing: Renal Impairment

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).

Dosing: Hepatic Impairment

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

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 (stomatisis, 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. Procarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011; Roila, 2010).

Dietary Considerations

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.

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

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

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 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.

Warnings/Precautions

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.

Monitoring Parameters

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

Pregnancy Risk Factor

D

Pregnancy Considerations

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.

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, 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.