Evrysdi (risdiplam)

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Administer risdiplam orally once daily with or without food at approximately the same time each day. Risdiplam is available as 5 mg oral tablets and as a 60 mg powder for oral solution that yields 0.75 mg/mL when constituted.

If a dose is missed, administer the missed dose as soon as possible within 6 hours; otherwise, skip the dose and resume the regular schedule the next day. If the dose is not fully swallowed or vomiting occurs, do not repeat the dose; wait until the next day to take the next scheduled dose.

No dosing information is available for this tab.

Risdiplam is primarily metabolized by flavin monooxygenase (FMO) 1 and FMO3 and also by cytochrome P-450 (CYP) isoenzymes 1A1, 2J2, 3A4, and 3A7.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Mate Inhibitors/Dofetilide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The active tubular secretion of dofetilide is inhibited by renal cation transport inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of dofetilide with renal cation transport inhibitors may result in elevated levels and increased effects of dofetilide including QT prolongation or torsades de pointes.(1)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent administration of dofetilide with renal cation transport inhibitors is contraindicated. The manufacturer suggests that agents that have no effect on dofetilide plasma levels, such as aluminum and magnesium hydroxide antacids, omeprazole, or ranitidine, be used as alternatives to cimetidine. If dofetilide is to be discontinued, a washout of at least 2 days is recommendation prior to starting cimetidine.(1)

DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Cimetidine is believed to inhibit the cation transport system.(1) The concurrent administration of dofetilide (500 mcg twice daily) with cimetidine (400 mg twice daily) resulted in an increase in dofetilide plasma levels by 58%. The concurrent administration of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily) resulted in an increase in dofetilide plasma levels by 13%.(1) Therefore, the manufacturer of dofetilide states that the concurrent administration of dofetilide and cimetidine is contraindicated. The manufacturer suggests that agents that have no effect on dofetilide plasma levels, such as aluminum and magnesium hydroxide antacids, omeprazole, or ranitidine, be used as alternatives to cimetidine.(1) MATE renal transport inhibitors include: cimetidine, pyrimethamine, risdiplam, and vandetanib.(3)

Risdiplam/Dabigatran

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Risdiplam may inhibit the renal excretion of substrates of Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys.(1) Dabigatran is a MATE substrate.

CLINICAL EFFECTS: Concurrent use of risdiplam may result in increased levels of and toxicity from dabigatran (a MATE substrate), including increased risk of bleeding.(1)

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age greater than 74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight less than 50 kg.(2-5)

PATIENT MANAGEMENT: Avoid concurrent use of dabigatran, a MATE substrate, with risdiplam. If concurrent use cannot be avoided, monitor for toxicities of dabigatran or consider alternative anticoagulant therapy.(1) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Based upon in vitro data, risdiplam is expected to produce clinically significant inhibition of MATE1 and MATE2-K transporters at clinically relevant concentrations.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Mate Inhibitors/Chloroquine; Hydroxychloroquine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may inhibit the renal tubular secretion of chloroquine or hydroxychloroquine via the MATE1 transporter.(1,2,3)

CLINICAL EFFECTS: Concurrent use of MATE inhibitors may result in increased levels of and toxicity from chloroquine or hydroxychloroquine, including irreversible retinopathy, potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP), hypoglycemia, or myopathy.(1,2)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturers of chloroquine and hydroxychloroquine state that concomitant use of MATE inhibitors should be avoided.(1,2) The Israeli manufacturer of hydroxychloroquine states that hydroxychloroquine sulphate may also be subject to several of the known interactions of chloroquine. Caution is advised when coadministering hydroxychloroquine with MATE inhibitors.(5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of healthy volunteers, cimetidine (400 mg daily for 4 days) decreased the clearance of single-dose chloroquine (300 mg) by 53% and half-life by 49%, compared to subjects not on cimetidine.(6) MATE inhibitors linked to this monograph include: bictegravir, brepocitinib, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(7)

Mate Inhibitors/Selected Mate Substrates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) renal protein transporters in the kidneys may inhibit the transport of MATE substrates.(1) Acyclovir, cephalexin, and valacyclovir are MATE substrates.

CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from MATE substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of acyclovir, cephalexin, or valacyclovir with MATE renal transporter inhibitors. If concurrent use cannot be avoided, monitor for toxicity of the MATE substrate and consider dosage reduction of the MATE substrate.(1)

DISCUSSION: Based upon in vitro data, risdiplam is expected to produce clinically significant inhibition of MATE1 and MATE2-K transporters at clinically relevant concentrations.(1) Selected MATE substrates linked include: acyclovir, cephalexin, and valacyclovir.(1,2) MATE inhibitors include: cimetidine, pyrimethamine, risdiplam, and vandetanib.(2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Mate Inhibitors/Flecainide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal elimination of flecainide.(1)

CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from flecainide.(1)

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Monitor serum flecainide concentrations and observe the patients for signs of toxicity. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a pharmacokinetic study, concurrent use of cimetidine (1 gram daily) increased flecainide levels by 30% and increased half-life by 10%.(1) MATE inhibitors linked include: abemaciclib, bictegravir, brepocitinib, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(4,5)

Mate Inhibitors/Metformin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal tubular secretion of metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: Use an alternative agent if possible. If both drugs are given, monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Dosage of either agent may need to be adjusted.(1)

DISCUSSION: In a study of normal healthy volunteers, concurrent metformin and oral cimetidine increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2) MATE inhibitors include: brepocitinib, cimetidine, pyrimethamine, and risdiplam.(3)

Mate Inhibitors/Oxaliplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may inhibit the renal transport of oxaliplatin.(1) Oxaliplatin is a MATE substrate.(2,3)

CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from oxaliplatin, including QT prolongation and neutropenia.(1)

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: Concurrent use of oxaliplatin with MATE renal transporter inhibitors should be approached with caution and monitored closely. If concurrent use is warranted, monitor for toxicities of oxaliplatin and consider dosage reduction based on toxicity dose recommendations.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Oxaliplatin is a MATE substrate.(2,3) MATE inhibitors include: abemaciclib, bictegravir, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(6,7)

Mate Inhibitors/Procainamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal elimination of procainamide and its active metabolite, N-acetylprocainamide (NAPA).

CLINICAL EFFECTS: The pharmacological and toxic effects of procainamide and NAPA may be increased, including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).

PATIENT MANAGEMENT: Monitor serum procainamide and NAPA concentrations and observe the patients for signs of toxicity. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Administration of trimethoprim to patients receiving procainamide produced an increase in the area under the concentration-time curve and a decrease in the clearance of procainamide. At the same time, serum NAPA concentrations and clearance were decreased. MATE inhibitors include: pyrimethamine, risdiplam, and trimethoprim.(4)

*None.

There are no contraindication contraindications for this drug.

• Pregnancy

There are no moderate contraindications for this drug.

The most common adverse reactions reported with risdiplam in patients with later-onset spinal muscular atrophy (SMA), occurring in >=10% of patients and at a higher frequency than in the control group, were fever, diarrhea, and rash. In infantile-onset SMA, similar adverse reactions were observed, along with upper and lower respiratory tract infections, constipation, vomiting, and cough.

More Frequent

• Pneumonia

More Frequent

• Constipation
• Diarrhea
• Fever
• Lower respiratory infection
• Skin rash
• Upper respiratory infection
• Vomiting

Less Frequent

• Aphthous stomatitis
• Arthralgia
• Bronchitis
• Cough
• Urinary tract infection

Rare or Very Rare

• Cutaneous vasculitis

No enhanced messaging available.

The safety and effectiveness of risdiplam in pediatric patients (neonates and older) have been established. Use of risdiplam in patients >=2 months of age with spinal muscular atrophy (SMA) is supported by adequate and well-controlled studies. Use in infants <2 months of age is supported by pharmacokinetic and safety data from infants >=16 days of age, along with dosing simulations.

There are no adequate data on risdiplam use in pregnant women. Animal studies showed that risdiplam exposure during pregnancy led to embryofetal mortality, structural malformations, reduced fetal body weight, and long-term reproductive impairment in offspring at or above clinically relevant exposure levels.

Clinicians are encouraged to register patients and pregnant women are encouraged to register themselves in a pregnancy exposure registry by calling 1-833-760-1098 or visiting https://www.evrysdipregnancyregistry.com.

There are no data on risdiplam in human milk, its effects on breast-fed infants, or milk production. Risdiplam was distributed into rat milk. The benefits of breastfeeding should be weighed against the mother's need for risdiplam and potential risks to the infant.

The manufacturer makes no dosage adjustments for geriatric patients; the effects in geriatric patients have not been studied.

Clinical studies of risdiplam did not include patients >=65 years of age.