Sensipar (cinacalcet HCl)

Dosage of cinacalcet hydrochloride is expressed in terms of cinacalcet. Dosage of the drug must be individualized.

Because severe or prolonged nausea and vomiting can result in dehydration and worsening hypercalcemia, careful monitoring of electrolytes is recommended in patients with these adverse effects.

No dosing information is available for this tab.

Cinacalcet is metabolized by cytochrome P-450 (CYP) isoenzymes 1A2, 2D6, and 3A4. In vitro studies indicate that cinacalcet is a potent inhibitor of CYP2D6, but cinacalcet does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, or 3A4 nor does it induce CYP isoenzymes.

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

Cinacalcet; Evocalcet/Etelcalcetide

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: Etelcalcetide is a calcimimetic agent that binds to the extracellular domain of the calcium-sensing receptor (CaSR) and enhances activation of the receptor by extracellular calcium.(1) Cinacalcet and evocalcet also increase the sensitivity of the CaSR to extracellular calcium but bind to the CaSR but at the transmembrane region of the receptor.(2-4) Activation of the CaSR decreases parathyroid hormone (PTH) secretion and subsequently decreases calcium levels. Additive decreases in PTH with subsequent additive decreases in calcium levels may occur with concurrent use.

CLINICAL EFFECTS: Concurrent administration of etelcalcetide with another oral calcium-sensing receptor agonist may result in severe, life-threatening, hypocalcemia. Hypocalcemia can cause paresthesias, myalgias, muscle spasms, seizures, QT prolongation, and ventricular arrhythmias.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of etelcalcetide recommends discontinuation of cinacalcet at least 7 days prior to starting etelcalcetide. When transitioning from cinacalcet to etelcalcetide, initiate etelcalcetide at a starting dose of 5 mg.(1) The US manufacturer of cinacalcet recommends discontinuation of etelcalcetide for at least 4 weeks prior to initiating cinacalcet. Initiate cinacalcet at a starting dose of 30 mg daily.(2) The UK manufacturer of cinacalcet states that an appropriate washout period of etelcalcetide has not been studied and recommends completion of at least three subsequent hemodialysis sessions and ensuring normal serum calcium before initiating cinacalcet.(3) The manufacturer of evocalcet does not provide recommendations for concurrent use with etelcalcetide but similar additive effects are expected based on a similar mechanism as cinacalcet.(4) Consider similar washout periods when transitioning from etelcalcetide to evocalcet. Before initiating these calcimimetics, ensure corrected serum calcium is at or above the lower limit of normal. Closely monitor corrected serum calcium and concurrent therapies known to lower serum calcium. Serum calcium monitoring is recommended within 1 week after initiation of etelcalcetide and every 4 weeks during treatment.(1)

DISCUSSION: Concurrent administration of etelcalcetide with other oral calcium-sensing receptor agonists may result in severe, life-threatening, hypocalcemia. Pooled data from two placebo-controlled clinical studies in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis were reviewed with a mean duration of 23.6 weeks. More patients on etelcalcetide versus placebo developed at least one corrected serum calcium level less than 7 mg/dL (7.6% v. 3.1%, respectively), less than 7.5 mg/dL (27% v. 5.5%, respectively), and less than 8.3 mg/dL (79% v. 19%, respectively). Symptomatic reductions in serum calcium less than 8.3 mg/dL occurred in 7% of patients receiving etelcalcetide versus 0.2% of patients receiving placebo.(1)

Selected Moderate Cyp2d6 Inhibitors/Thioridazine

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: Moderate inhibitors of CYP2D6 may inhibit the metabolism of thioridazine.(1-4)

CLINICAL EFFECTS: The concurrent administration of moderate CYP2D6 inhibitors with thioridazine may result in elevated levels of thioridazine.(1-4) Elevated levels of thioridazine may augment thioridazine-induced prolongation of the QTc interval, increasing the risk of serious, potentially fatal, cardiac arrhythmias such as torsades de pointes.(1)

PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. 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.(5) 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. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: The concurrent use of thioridazine with CYP2D6 inhibitors is contraindicated.(1) Use an alternative agent, or change to another antipsychotic agent. If the patient is on oral terbinafine for the treatment of onychomycosis, use a terbinafine formulation with a non-systemic route. If alternative treatments are not possible for either agent and concurrent therapy is deemed medically necessary, strongly 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. Thioridazine should not be initiated in patients with a QTc interval greater than 450 msec and should be discontinued in patients found to have a corrected QTc greater than 500 msec.(3)

DISCUSSION: A study in six slow and 13 rapid metabolizers of debrisoquin, a marker of CYP2D6 activity, showed that slow metabolizers of debrisoquin had 2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and area-under-curve (AUC), respectively, than rapid metabolizers.(4) A study in 9 healthy male subjects showed a thioridazine dose-related prolongation of the QTc interval. One subtherapeutic thioridazine 10 mg dose increased QTc 9 msec (range -1 to 19 msec), and a single low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11 to 33 msec).(7) Coadministration of cinacalcet (90 mg once daily) and desipramine (50 mg), a CYP2D6 substrate, resulted in an approximate 3.6-fold increase in the exposure of desipramine in healthy subjects who were CYP2D6 extensive metabolizers.(8) In another study, cinacalcet (50 mg daily) increased AUC of single-dose dextromethorphan (30 mg), a CYP2D6 substrate, by 4.93-fold in 2D6 extensive metabolizers.(9)

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

Selected Moderate Cyp2d6 Inhibitors/Tamoxifen

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

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of moderate CYP2D6 inhibitors in patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(14) Cancer Care Ontario breast cancer guidelines state concurrent use of moderate CYP2D6 inhibitors should be approached with caution and alternative options should be considered.(15) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(16) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(17)

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(18) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(19-20) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(21-23) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(24-28) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(17) Moderate inhibitors of CYP2D6 include abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, levomepromazine, mirabegron, moclobemide, rolapitant, and tipranavir/ritonavir.(29-30)

Strong & Moderate Cyp2d6 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient has hepatic impairment, is also taking an inhibitor of CYP3A4 and/or is an extensive or intermediate metabolizer of CYP2D6, eliglustat metabolism can be further inhibited.(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 dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be continued at 84 mg once daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(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. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(5)

DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(1,3,4) Moderate inhibitors of CYP2D6 include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, escitalopram, levomepromazine, levomethadone, mirabegron, moclobemide, and rolapitant.(1,3,4)

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

Cinacalcet/Higher Strength Select Tricyclics

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

MECHANISM OF ACTION: Cinacalcet may inhibit the CYP2D6 mediated metabolism of amitriptyline, desipramine, nortriptyline, and trimipramine.(1,2)

CLINICAL EFFECTS: Concurrent use of cinacalcet and amitriptyline, desipramine, nortriptyline, or trimipramine may result in elevated levels of and toxicity from these tricyclic antidepressants.(1,3)

PREDISPOSING FACTORS: Higher doses of either agent are expected to increase the severity of the interaction. In patients with moderate to severe hepatic impairment, cinacalcet exposure is 2.4 to 4.2-fold higher and the mean half-life increased from 49 to 65-84 hours compared with healthy volunteers.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer describes cinacalcet as a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications predominantly metabolized by CYP2D6, particularly if they have a narrow therapeutic index.(1) Cinacalcet has a long elimination half-life of 49 hours so the time to maximal inhibition of a CYP2D6 metabolized drug may not be seen for a week or more after starting or increasing the dose of cinacalcet. In an interaction study, cinacalcet 90 mg daily increased desipramine exposure (AUC, area-under-curve) 264%.(1) Instruct patients to report seizures, fainting, irregular heartbeat, new or worsening blurred vision, urinary retention, mental or mood changes, confusion, dry mouth or constipation.

DISCUSSION: In an interaction study, fourteen subjects who were extensive metabolizers of CYP2D6 received one dose of desipramine 50 mg, either alone or after 7 days of pretreatment with cinacalcet 90 mg daily. Compared with desipramine alone, cinacalcet administration increased desipramine exposure (AUC, area-under-curve) and maximum concentration (Cmax) 3.6 and 1.8-fold respectively. Desipramine half-life was also longer when it was coadministered with cinacalcet (21.0 versus 43.3 hs). Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33% versus 86%).(2) In an interaction study, subjects who were extensive metabolizers of CYP2D6 received one dose of amitriptyline 50 mg with a single dose of cinacalcet (25 or 100 mg) resulting in a change in AUC and Cmax for amitriptyline of 21-22% and 13-21%, respectively. The change in AUC and Cmax for nortriptyline was 17-23% and 11-15%, respectively.(1)

Cinacalcet/Lower Strength Select Tricyclics

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

MECHANISM OF ACTION: Cinacalcet may inhibit the CYP2D6 mediated metabolism of amitriptyline, desipramine and nortriptyline.(1,2)

CLINICAL EFFECTS: Concurrent use of cinacalcet and amitriptyline, desipramine, or nortriptyline may result in elevated levels of and toxicity from these tricyclic antidepressants.(1,3)

PREDISPOSING FACTORS: Higher doses of either agent are expected to increase the severity of the interaction. In patients with moderate to severe hepatic impairment, cinacalcet exposure is 2.4 to 4.2-fold higher and the mean half-life increased from 49 to 65-84 hours compared with healthy volunteers.(1) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer describes cinacalcet as a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications predominantly metabolized by CYP2D6, particularly if they have a narrow therapeutic index.(1) Cinacalcet has a long elimination half-life of 49 hours so the time to maximal inhibition of a CYP2D6 metabolized drug may not be seen for a week or more after starting or increasing the dose of cinacalcet. In an interaction study, cinacalcet 90 mg daily increased desipramine exposure (AUC, area-under-curve) 264%.(1) Instruct patients to report seizures, fainting, irregular heartbeat, new or worsening blurred vision, urinary retention, mental or mood changes, confusion, dry mouth or constipation.

DISCUSSION: In an interaction study, fourteen subjects who were extensive metabolizers of CYP2D6 received one dose of desipramine 50 mg, either alone or after 7 days of pretreatment with cinacalcet 90 mg daily. Compared with desipramine alone, cinacalcet administration increased desipramine exposure (AUC, area-under-curve) and maximum concentration (Cmax) 3.6 and 1.8-fold respectively. Desipramine half-life was also longer when it was coadministered with cinacalcet (21.0 versus 43.3 hs). Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33% versus 86%).(2) In an interaction study, subjects who were extensive metabolizers of CYP2D6 received one dose of amitriptyline 50 mg with a single dose of cinacalcet (25 or 100 mg) resulting in a change in AUC and Cmax for amitriptyline of 21-22% and 13-21%, respectively. The change in AUC and Cmax for nortriptyline was 17-23% and 11-15%, respectively.(1)

Cinacalcet/Strong Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of cinacalcet by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of and toxicity from cinacalcet.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: PTH and serum calcium concentrations should be closely monitored if a strong CYP3A4 inhibitor is initiated or discontinued in patients receiving cinacalcet therapy. The dosage of cinacalcet may need to be adjusted.(1)

DISCUSSION: In a study, administration of cinacalcet on day 5 of a seven day course of ketoconazole (200 mg twice daily) increased cinacalcet area-under-curve (AUC) and maximum concentration (Cmax) by 2.3-fold and by 2.2-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(2)

Moderate Cyp2d6 Inhibitors/Brexpiprazole

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

MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of brexpiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a moderate CYP2D6 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are receiving concomitant treatment with a strong or moderate CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor. Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in extensive metabolizers of CYP2D6.(1)

PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a moderate CYP2D6 inhibitor: - in patients with schizophrenia or major depressive disorder who are taking a moderate CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. - no empiric dosage adjustment is recommended for patients receiving moderate CYP2D6 inhibitors without a strong or moderate inhibitor of CYP3A4. The dose of brexpiprazole should be adjusted to its original level if the CYP2D6 inhibitor is discontinued.(1) Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(2)

DISCUSSION: Coadministration of quinidine, a strong inhibitor of CYP2D6, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(2) Moderate CYP2D6 inhibitors linked to this monograph include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, levomepromazine, mirabegron, moclobemide, and rolapitant.

Moderate Cyp2d6 Inhibitors/Oliceridine

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

MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1)

PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, lorcaserin, levomepromazine, mirabegron, moclobemide, and rolapitant.(4)

Selected Cyp2d6 Inhibitors/Metoprolol

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

MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2)

PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1,2)

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(3)

DISCUSSION: In a study, citalopram (40 mg daily for 22 days) increased plasma concentrations of metoprolol 2-fold.(4) In a study in healthy subjects, duloxetine (60 mg daily), escitalopram (20 mg daily), and sertraline (100 mg daily) increased the AUC of a single dose of metoprolol by 180%, 89%, and 48-67%, respectively.(5) In a study in 7 healthy subjects, ranitidine (150 mg BID) increased the area-under-curve (AUC) of metoprolol by 50% compared to values obtained 10 months earlier in the same subjects with metoprolol alone.(6) In a study in 6 subjects, pretreatment with ranitidine for 1 week increased the maximum concentration (Cmax) of metoprolol. However, in a follow-up study in 12 healthy subjects, ranitidine had no effect on metoprolol pharmacokinetics when administered concurrently for 1 week.(7) In a study in 6 healthy subjects, ranitidine increased the AUC and Cmax of metoprolol by 50%. There were no changes in metoprolol pharmacodynamics.(8) In a study in healthy subjects, ranitidine increased metoprolol Cmax by about 30%.(9) In a study in 12 healthy males, ranitidine had no effect on the pharmacokinetics or pharmacodynamics of metoprolol.(10) In healthy subjects, ranolazine (750 mg twice daily) increased plasma levels of a single dose of metoprolol (100 mg) by 1.8-fold.(11) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, diphenhydramine, duloxetine, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and sertraline. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Cyp2d6 Inhibitors/Propranolol

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

MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of propranolol.(1)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from propranolol, including hypotension and bradycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with propranolol and CYP2D6 inhibitors. The dosage of propranolol may need to be adjusted.(1)

DISCUSSION: In a pharmacokinetic study in 16 healthy volunteers, concurrent use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve (AUC) of propranolol by 2.29-fold.(2) In a pharmacokinetic study in 6 healthy subjects, concurrent use of quinidine increased propranolol AUC 2-fold.(3) A retrospective review of concurrent use of propranolol and antidepressants evaluated the risk of hospitalization or emergency room visit within 30 days of concurrent prescription. In patients receiving antidepressants with moderate to strong CYP2D6 inhibitory effects, patient were an increased risk compared to patients receiving no antidepressants (Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI 0.82-1.88).(4) Case reports of bradycardia and cardiac adverse effects have been reported with concurrent use of propranolol and the antidepressants fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, mavorixafor, and paroxetine. Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, levomepromazine, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6)

Selected Moderate To Strong Cyp2d6 Inhibitors/Tramadol

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

MECHANISM OF ACTION: Abiraterone, asunaprevir, berotralstat, bupropion, cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, fluoxetine, hydroquinidine, levomepromazine, levomethadone, lorcaserin, mirabegron, paroxetine, quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its more active O-demethylated metabolite (M1).(1-6) M1 is up to 6 times more potent than tramadol in producing analgesia.(1)

CLINICAL EFFECTS: Tramadol analgesic efficacy may be decreased due to lower mu-opioid receptor mediated analgesia.(1,9,10) Higher concentrations of tramadol may be associated with increased inhibition of norepinephrine and serotonin reuptake, increasing risk for seizures and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)

PREDISPOSING FACTORS: Risk for seizure may be increased with tramadol doses above the recommended range, in patients with metabolic disorders, alcohol or drug withdrawal, infection of the central nervous system, or with a history of seizures or head trauma.(1) Treatment with multiple medications which increase serotonin levels, or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(1,7) Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer.(14) Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.(14)

PATIENT MANAGEMENT: If a CYP2D6 inhibitor is started in a patient stabilized on long term tramadol therapy, monitor for loss of analgesic efficacy. When initiating tramadol in a patient stabilized on a moderate or strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized patients may need added doses of rescue analgesics to achieve adequate pain control.(9,10) To decrease risk for serotonin syndrome, consider change to an alternative analgesic for patients taking other serotonin increasing drugs in addition to concomitant tramadol and a CYP2D6 inhibitor. If a CYP2D6 inhibitor is discontinued, consider lowering the dose of tramadol until patient achieves stable drug effects. The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(12)

DISCUSSION: Tramadol and its M1 metabolite both contribute to analgesic efficacy. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP2D6 converts tramadol to M1.(1,8) A prospective study evaluated the impact of 2D6 genotype on tramadol analgesia after abdominal surgery. Rescue doses of opioids were required in 47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of 2D6.(9) A follow-up study included 2D6 EM patients who received concomitant treatment with 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. The authors noted some EM patients were converted to the PM phenotype.(10) In both studies, higher M1 levels were associated with greater analgesic efficacy and decreased need for rescue opioid treatment.(9,10) A study in 12 healthy volunteers found that a single dose of tramadol (50 mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively, than tramadol given alone. The AUC and Cmax of M1 were decreased by 64 % and 78 %, respectively.(13) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(12)

Cinacalcet is contraindicated in patients with serum calcium concentrations below the lower limit of normal.

• Congenital long QT syndrome

• Esophagitis
• Hypocalcemia
• Peptic ulcer
• Prolonged QT interval
• Seizure disorder

• Adynamic bone disease
• Chronic heart failure
• Disease of liver
• Hypophosphatemia
• Hypotension

The most commonly reported adverse effects of cinacalcet in patients with hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism or in dialysis patients with secondary hyperparathyroidism are nausea and vomiting.

In 3 controlled studies in dialysis patients with secondary hyperparathyroidism, adverse effects occurring in 5% of more of patients receiving cinacalcet for up to 6 months and at an incidence higher than that reported with placebo included nausea, vomiting, diarrhea, myalgia, dizziness, hypertension, asthenia, anorexia, noncardiac chest pain, and access infection. In the EVOLVE study in dialysis patients with secondary hyperparathyroidism, adverse effects reported in 5% or more of patients receiving cinacalcet for up to 64 months and at an incidence higher than that reported with placebo included nausea, vomiting, diarrhea, dyspnea, cough, hypotension, headache, hypocalcemia, muscle spasms, abdominal pain (including upper abdominal pain), hyperkalemia, upper respiratory tract infection, dyspepsia, dizziness, decreased appetite, asthenia, and constipation.

Adverse effects in patients with hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism generally are similar to those observed in dialysis patients.

Less Frequent

• Dehydration
• Hyperkalemia
• Hypertension
• Hypocalcemia
• Non-cardiac chest pain
• Seizure disorder

Rare or Very Rare

• Adynamic bone disease
• Angioedema
• Cardiac arrhythmia
• Fracture
• Gastrointestinal hemorrhage
• Hypotension
• Pseudogout
• Worsening of chronic heart failure

More Frequent

• Diarrhea
• Dizziness
• Myalgia
• Nausea
• Paresthesia
• Vomiting

Less Frequent

• Acute abdominal pain
• Anorexia
• Back pain
• Constipation
• Dyspepsia
• Dyspnea
• General weakness
• Headache disorder
• Muscle spasm
• Upper abdominal pain
• Upper respiratory infection

Rare or Very Rare

• Skin rash
• Urticaria

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Safety and efficacy of cinacalcet in pediatric patients younger than 18 years of age have not been established, and the drug is not indicated for use in pediatric patients. In 2013, FDA announced suspension of pediatric clinical trials of the drug after the death of a 14-year-old adolescent with severe hypocalcemia occurred during a trial.

Category C. (See Users Guide.) Women who become pregnant while receiving cinacalcet are encouraged to enroll in the manufacturer's pregnancy surveillance program. Patients or their clinicians should call 800-772-6436 to enroll.

Cinacalcet is distributed into milk in rats; it is not known whether cinacalcet is distributed into human milk. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Women who opt to continue cinacalcet treatment while nursing are encouraged to enroll in the manufacturer's lactation surveillance program. Patients or their clinicians should call 800-772-6436 to enroll.

No substantial differences in the pharmacokinetic profile, safety, and efficacy of cinacalcet have been observed in patients 65 years of age or older relative to younger adults. However, greater sensitivity of some older patients cannot be ruled out.