Tamoxifen Citrate (tamoxifen citrate)

Dosage of tamoxifen citrate is expressed in terms of tamoxifen.

Tamoxifen citrate is commercially available as oral tablets containing 10 mg or 20 mg of tamoxifen, equivalent to 15.2 or 30.4 mg of tamoxifen citrate, respectively. Tamoxifen citrate is also commercially available as an oral solution with each 10 mL containing 20 mg of tamoxifen (equivalent to 30.4 mg tamoxifen citrate).

Tamoxifen is administered orally without regard to meals. Dosages exceeding 20 mg daily should be given in divided doses (morning and evening).

Commercially available tamoxifen tablets should be protected from light and stored in well-closed containers at controlled room temperature (20-25degreesC).

Commercially available tamoxifen oral solution should be protected from light and stored in the original packaging at 20-25degreesC (excursions permitted between 15-30degreesC). Do not freeze or refrigerate the oral solution. Discard any unused portions of the oral solution 3 months after first opening the bottle.

Tamoxifen is extensively metabolized by multiple cytochrome P-450 (CYP) isoenzymes, including 2B6, 2C9, 2C19, 2D6, and 3A. The metabolism of tamoxifen to form N-desmethyltamoxifen (major metabolite found in plasma) is mediated mainly by CYP3A. Polymorphic CYP2D6 is involved in the formation of endoxifen and 4-hydroxytamoxifen (minor metabolites) and is the primary enzyme responsible for catalyzing the conversion of N-desmethyltamoxifen to endoxifen.

Phase II metabolizing enzymes, including sulfotransferase family 1A member 1 (SULT1A1), uridine diphosphate-glucuronosyltransferase (UGT) 2B7, and UGT1A4, are involved in the clearance of tamoxifen from plasma. Tamoxifen inhibits P-glycoprotein.

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

Estrogen Receptor Blockers (Erbs)/Fluoroestradiol F-18

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: Drugs that bind to the estrogen receptor (ER) may compete with the binding of radioactive diagnostic agent fluoroestradiol F-18.(1)

CLINICAL EFFECTS: Concurrent use of estrogen receptor blockers such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs) may reduce the detection of ER-positive lesions with fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Before administering fluoroestradiol F-18, discontinue drugs that bind to the ER, such as SERMs and SERDs, for at least 5 biological half-lives.(1) The following washout periods apply when discontinuing ERBs, prior to fluoroestradiol F-18 administration: - Bazedoxifene = 7 days - Clomiphene = 25 days - Elacestrant = 11 days - Enclomiphene = 25 days - Fulvestrant = 28 weeks - Imlunestrant = 7 days - Ospemifene = 5 days - Raloxifene = 7 days - Tamoxifen = 8 weeks - Toremifene = 5 weeks

DISCUSSION: The following ERBs are linked to this monograph: SERDs: elacestrant, imlunestrant, and fulvestrant. SERMs: bazedoxifene, clomiphene, enclomiphene, ospemifene, raloxifene, tamoxifen and toremifene.

Selected Agents/Mibefradil

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: Mibefradil has been shown to inhibit the activity of CYP P-450-3A4 and CYP P-450-2D6 and may inhibit the metabolism of these agents.(1-2)

CLINICAL EFFECTS: Concurrent administration may result in elevated levels of these agents.(1,2) Withdrawal of mibefradil may result in decreased levels of these agents. Concurrent administration of the mibefradil with the HMG-CoA reductase inhibitors may result in elevated levels of the HMG-CoA reductase inhibitors, which may result in rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients who received concurrent therapy with mibefradil and these agents should be monitored for decreased levels and effectiveness of these medications during the two weeks following the withdrawal of mibefradil. Dosage adjustments of the medications may be necessary. The manufacturer of mibefradil stated that concurrent administration of mibefradil with either lovastatin or simvastatin was contraindicated and that concurrent administration of mibefradil with either atorvastatin or cerivastatin should have generally been avoided.(1) Fluvastatin or pravastatin, which are not significantly metabolized by CYP P-450-3A4, may have been used as alternatives in patients receiving mibefradil.

DISCUSSION: Mibefradil was shown to inhibit CYP P-450-3A4 and CYP P-450-2D6 thus may inhibit the metabolism of agents metabolized at these sites. Withdrawal of mibefradil may result in decreased levels of these agents as the CYP P-450 system returns to normal. Following the discontinuation of mibefradil, seven to 14 days are required for sufficient elimination of mibefradil metabolites to minimize mibefradil effects on the CYP P-450 system. Dosage adjustments may need to be made during this period.(2) The manufacturer stated that there were seven reports of rhabdomyolysis in patients receiving concurrent therapy with simvastatin and mibefradil. Four patients were also receiving cyclosporine. Because lovastatin follows the same metabolic pathway as simvastatin, a similar interaction would be expected. Atorvastatin and cerivastatin are metabolized by CYP P-450-3A4 to active and inactive metabolites.(1)

Tamoxifen/Anastrozole; Letrozole

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: Tamoxifen may induce the metabolism of anastrozole(1) and letrozole(2) by induction of CYP3A4.

CLINICAL EFFECTS: Concurrent use of tamoxifen may result in decreased plasma levels and effectiveness of anastrozole(1,3) and letrozole.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of anastrozole(1) and tamoxifen(3) state that these agents should not be coadministered. The manufacturer of letrozole does not recommend concurrent therapy with tamoxifen(4) and the manufacturer of tamoxifen states they should not be used concurrently.(3) Patients may benefit more from sequential therapy, rather than concurrent therapy.(2,5)

DISCUSSION: Based on clinical and pharmacokinetic data from the ATAC trial, tamoxifen should not be administered with anastrozole. Concurrent use decreased anastrozole plasma levels by 27%. The combination had no efficacy benefit when compared to tamoxifen administration alone. Tamoxifen pharmacokinetics were not affected.(1,3) A study in 12 subjects examined the concurrent administration of tamoxifen and letrozole for six weeks. Concurrent use decreased the mean concentration of letrozole by 37.6%.(3,4) Although suppression of estradiol, estrone, and estrone sulfate were not effected, the authors speculated that patients may not receive the full benefit of combination therapy.(4) A study in 23 patients found that letrozole had no effect on tamoxifen levels. However, the antitumor effects of combination therapy were less than expected.(6) The therapeutic effect of letrozole is not affected if letrozole is administered immediately after tamoxifen.(5)

Tamoxifen/Strong Cyp3a4 Inducers

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: Strong inducers of CYP3A4 may induce the metabolism of tamoxifen.(1)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort may result in decreased levels and effectiveness of tamoxifen.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Strong inducers of CYP3A4 should not be used in patients receiving tamoxifen.(1)

DISCUSSION: In a study in healthy males, rifampin (600 mg daily for 5 days) decreased maximum concentration (Cmax) and AUC of a single dose of tamoxifen (80 mg) by 86% and 55%, respectively. The AUC of N-demethyltoremifene decreased by 62%.(1,2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3,4)

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

Tamoxifen/Ribociclib

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

MECHANISM OF ACTION: Concurrent use of ribociclib with tamoxifen may result in additive effects on the QTc interval.(1,2) Additionally, ribociclib is a strong CYP3A4 inhibitor and may increase the plasma concentration of tamoxifen.(1)

CLINICAL EFFECTS: The concurrent use of ribociclib with tamoxifen may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes. As well, concurrent use may result in elevated levels of and adverse effects from tamoxifen.(1)

PREDISPOSING FACTORS: 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.(3) 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, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of ribociclib states that ribociclib is not indicated for concomitant use with tamoxifen.(1)

DISCUSSION: Ribociclib has been shown to prolong the QTc interval in a concentration-dependent manner. At steady state, the mean increase in QTc interval exceeded 20 msec.(1) In a phase 3, randomized, double-blind, placebo-controlled trial (MONALEESA-7), a QTcF interval increase of greater than 60 ms from baseline was observed in 14/87 (16%) of patients in the ribociclib and tamoxifen combination group, compared to 18/245 (7%) of patients receiving ribociclib plus a non-steroidal aromatase inhibitor and 6/90 (7%) of patients receiving tamoxifen alone. None of the patients developed clinical symptoms or arrhythmias.(1,2) In a clinical trial, ribociclib (600 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of tamoxifen by approximately 2-fold.(1)

Tamoxifen/Select Moderate Cyp2d6 Inhibitors

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 CYP2D6 inhibitors that prolong the QT interval include adagrasib, dronedarone, levomethadone, and quinine.(29-30)

Tamoxifen/Selected Moderate Cyp2d6 Inhibitors

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)

Tamoxifen/Selected Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) 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. CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of strong 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. PREDISPOSING FACTORS: Concurrent use of strong 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 Canadian and UK manufacturers of fluoxetine state that whenever possible co-administration with tamoxifen should be avoided.(14-15) The National Comprehensive Cancer Network's (NCCN) breast cancer guidelines advise caution when coadministering strong CYP2D6 inhibitors with tamoxifen. 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.(16) Cancer Care Ontario breast cancer guidelines state concurrent use of strong CYP2D6 inhibitors should be avoided.(17) 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.(18) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient. 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 strong CYP2D6 inhibitors should be avoided.(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.

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.(19) 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).(20-21) 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.(22-24) 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,(25-29) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Strong inhibitors of CYP2D6 include bupropion, dacomitinib, fluoxetine, paroxetine, peruvian bark extract, and terbinafine.(30-31) 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.(17) 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).(18-19) 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.(20-22) 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,(23-27) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Strong CYP2D6 inhibitors include hydroquinidine, mavorixafor, and quinidine.(28-29)

Tamoxifen; Toremifene/Coumarin Anticoagulants

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

MECHANISM OF ACTION: Tamoxifen and toremifene may inhibit the CYP2C9 mediated metabolism of warfarin.

CLINICAL EFFECTS: The concurrent use of tamoxifen or toremifene and warfarin may result in an increased risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Closely monitor INR when tamoxifen or toremifene are added to or discontinued from concurrent anticoagulant therapy.(1,2) In high risk women taking tamoxifen for a reduction in breast cancer risk and in women with ductal carcinoma in situ (DCIS), concurrent therapy with coumarin anticoagulants is contraindicated.(1)

DISCUSSION: There is one case report of an increase in prothrombin time when tamoxifen was added to warfarin therapy. This case led to a retrospective chart review of five patients. Two patients also had increases in prothrombin time. The other three patients required a smaller than normal dose of warfarin to maintain appropriate prothrombin times.(3) In another case report, a patient developed hematuria and hematemesis three weeks after the addition of tamoxifen to warfarin therapy.(4) In a retrospective review of 22 patients who received concurrent therapy with warfarin and tamoxifen, no problems were noted. Two patients had increased prothrombin times with no signs of bleeding. One patient experienced a subconjunctival hemorrhage, despite no problems with control of prothrombin times. Another patient experienced difficulty in control of prothrombin times and a thigh hematoma. Another patient developed an intraocular hemorrhage and hemorrhagic rashes after the addition of tamoxifen to warfarin therapy.(5) One set of authors postulated that the antitumor activity of tamoxifen may be reduced if warfarin competitively inhibits the formation of the active metabolite of tamoxifen; however, this has not been demonstrated.(3) In a case report, a 50-year-old woman with a history of breast cancer started warfarin after mitral valve replacement. She had been on toremifene but it was held during hospitalization for the MVR due to unavailable supply. Warfarin was dosed up to 21 mg/week in the absence of toremifene. After hospital discharge, patient resumed toremifene and warfarin dose had to be reduced by 37.5% to avoid supratherapeutic INR.(6)

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

Tamoxifen/Aminoglutethimide

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

MECHANISM OF ACTION: Aminoglutethimide may induce the metabolism of tamoxifen by CYP3A4.(1) Concurrent use may result in additive toxicities.

CLINICAL EFFECTS: Concurrent use of aminoglutethimide and tamoxifen may result in increased toxicity while not increasing efficacy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be closely monitored for toxicity and decreased tamoxifen efficacy.

DISCUSSION: In a study in 6 women with breast cancer, concurrent aminoglutethimide (1 gram/day) increased the clearance of tamoxifen (20 mg/day to 90 mg/day) by 2.2-fold. The area-under-curve (AUC) of tamoxifen decreased 73%. Levels of most tamoxifen metabolites were also decreased.(2) Several clinical trials examining concurrent use of aminoglutethimide and tamoxifen have documented increased toxicity(3-8) and/or no increase in efficacy.(3-11)

Tamoxifen/Hydroxychloroquine

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

MECHANISM OF ACTION: Hydroxychloroquine, a weak inhibitor 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 hydroxychloroquine may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 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 weak CYP2D6 inhibitors should be closely monitored.(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.

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.(17) 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).(18-19) 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.(20-22) 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,(23-27) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up.

Tamoxifen/Selected Weak Cyp2d6 Inhibitors

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

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

PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 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 weak CYP2D6 inhibitors should be closely monitored.(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. 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 weak CYP2D6 inhibitors should be closely monitored.(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.

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. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, cimetidine, clobazam, clomipramine, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sarpogrelate, sertraline, verapamil and viloxazine.(29) 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.(17) 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).(18-19) 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.(20-22) 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,(23-27) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak CYP2D6 inhibitors include: amiodarone, chlorpromazine, citalopram, escitalopram, flecainide, methadone, panobinostat, propafenone, telithromycin, vemurafenib, and venlafaxine.(28-29)

*Known hypersensitivity to tamoxifen or other ingredients in the formulation.

*When used in women with ductal carcinoma in situ (DCIS) and women at high risk for breast cancer, history of deep-vein thrombosis (DVT) or pulmonary embolism (PE).

*When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.

• Deep venous thrombosis
• Lactation

• Cerebrovascular accident
• Pregnancy
• Pulmonary thromboembolism
• Thrombocytopenic disorder
• Thromboembolic disorder

• Cataracts
• Congenital long QT syndrome
• Disease of liver
• Hypercalcemia
• Leukopenia
• Prolonged QT interval

Common adverse effects of tamoxifen include hot flushes (flashes), mood disturbances, vaginal discharge, vaginal bleeding, nausea, and fluid retention.

More Frequent

• General weakness

Less Frequent

• Cataracts
• Osteoporosis
• Tumor flare reaction

Rare or Very Rare

• Abnormal hepatic function tests
• Acute pancreatitis
• Anemia
• Angioedema
• Bullous pemphigoid
• Cerebrovascular accident
• Cholestasis
• Deep venous thrombosis
• Disorder of cornea
• Endometrial carcinoma
• Endometrial hyperplasia
• Endometrial polyps
• Erythema multiforme
• Hepatic necrosis
• Hepatitis
• Hypercalcemia
• Hypersensitivity drug reaction
• Interstitial pneumonitis
• Leukopenia
• Pulmonary thromboembolism
• Retinal disorder
• Retinal thrombosis
• Steatosis of liver
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thromboembolic disorder
• Thrombotic disorder

More Frequent

• Mood changes
• Peripheral edema
• Vaginal discharge
• Vaginal dryness

Less Frequent

• Alopecia
• Bone pain
• Cough
• Genital organ pruritus
• Headache disorder
• Irregular menstrual periods
• Menstrual disorder
• Oligomenorrhea
• Skin rash
• Vomiting
• Weight gain
• Weight loss

Rare or Very Rare

• Abnormal vaginal bleeding
• Amenorrhea
• Body fluid retention
• Depression
• Dizziness
• Drug-induced hot flash
• Dysgeusia
• Erectile dysfunction
• Hypertriglyceridemia
• Libido changes
• Nausea

No enhanced messaging available.

The safety and effectiveness of tamoxifen have not been established in pediatric patients.

Tamoxifen has been used for the treatment of Albright syndrome+ (also known as McCune-Albright syndrome) and precocious puberty in girls 2-10 years of age; however, the manufacturer of tamoxifen oral solution states that the safety and effectiveness of the drug for the treatment of girls with McCune-Albright syndrome, including long-term effects, have not been established. In a noncomparative study, 28 girls 2-10 years of age with Albright syndrome and precocious puberty (manifested by physical signs of pubertal development, episodes of vaginal bleeding, and/or advanced bone age) received tamoxifen 20 mg once daily for up to 12 months. Tamoxifen therapy was associated with a 50% reduction in frequency of vaginal bleeding episodes and reductions in bone age maturation and linear growth velocity. An increase in mean uterine volume was observed following 6 months of therapy, with doubling of uterine volume observed after one year of therapy; however, a causal relationship to the drug has not been established. Because tamoxifen has been associated with an increased incidence of endometrial and uterine malignancies in adults, the manufacturer recommends continued monitoring for long-term uterine effects in pediatric patients receiving tamoxifen for the treatment of Albright syndrome. The manufacturer of tamoxifen tablets state that the effects of tamoxifen beyond one year of treatment in girls with McCune-Albright syndrome have not been established.

In animal studies, direct exposure of neonatal mice and rats to tamoxifen resulted in lesions in the female reproductive tract (similar to those observed with DES in humans) and functional defects of the male reproductive tract (e.g., testicular atrophy, arrest of spermatogenesis).

Tamoxifen can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies using tamoxifen in pregnant women. There have been reports of spontaneous abortions, birth defects, fetal deaths, and vaginal bleeding in the postmarketing setting.

In nonhuman primate studies, administration of tamoxifen at doses approximately twice the maximum recommended human dosage was associated with spontaneous abortion. In reproductive toxicity studies in rats and rabbits, tamoxifen administered at doses at or below human doses resulted in increased embryotoxicity, abortions, and alterations in learning behavior in offspring. Furthermore, studies in rodent models demonstrated reproductive tract abnormalities in male and female offspring, resembling changes historically associated with in utero exposure to DES.

Advise women not to become pregnant while receiving tamoxifen or within 2 months after discontinuance of therapy with the drug. When tamoxifen is administered during pregnancy or if the patient becomes pregnant while receiving the drug or within approximately 2 months after discontinuance of therapy with tamoxifen, advise the patient of the potential hazard to the fetus, including the possible long-term risk of a DES-like syndrome.

It is not known if tamoxifen is distributed into human milk. The effects of tamoxifen on the breast-fed infant are unknown; however, data from juvenile animal studies suggest a potential for serious long-term adverse effects for breast-fed infants exposed to tamoxifen through breast milk. Direct exposure (not via breast milk) of neonatal mice and rat pups to tamoxifen has resulted in adverse reproductive tract effects (i.e., lesions in female pups that are similar to those observed in humans after intrauterine DES exposure; functional defects of the reproductive tract, including testicular atrophy and arrested spermatogenesis, in male pups).

Tamoxifen inhibits lactation. In 2 placebo-controlled trials, inhibition of early postpartum milk production was observed in women who received tamoxifen within 24 hours of delivery for a duration of 5-18 days. The effect of tamoxifen on established milk production is not known.

Because of the potential for serious adverse reactions to tamoxifen in nursing infants, advise women not to breast-feed during tamoxifen therapy and for 3 months after the last dose.

The manufacturers make no specific dosage recommendations for geriatric patients.

In the BCPT, 16% of the study participants were 65 years of age or older and 6% were at least 70 years of age. Reductions in the incidence of breast cancer were observed in women receiving tamoxifen across all age groups. Across all other outcomes, the results in the subset of women 65 years of age or older reflect the results observed in the subset of women at least 50 years of age. In this study, no overall differences in safety were observed between geriatric patients and younger adults.

In the NSABP B-24 study evaluating tamoxifen in patients with DCIS, 23% of the study participants were 65 years of age or older and 10% were at least 70 years of age. Because invasive breast cancer occurred in relatively few tamoxifen- or placebo-treated women 65 years of age or older, the results were insufficient to determine whether geriatric patients respond differently than younger adults for this outcome. Across all other outcomes, no overall differences were observed between geriatric patients and younger adults. In this study, no overall differences in safety were observed between geriatric patients and younger adults.