Alogliptin (alogliptin benzoate)

Dosage of alogliptin benzoate is expressed in terms of alogliptin.

When administered as a single-entity preparation, alogliptin may be administered orally once daily without regard to meals. Alogliptin tablets should be swallowed whole and should not be split.

When alogliptin is administered in fixed combination with metformin hydrochloride, the combination should be administered twice daily with food; dosage should be titrated gradually to minimize adverse GI effects of the metformin component. Fixed-combination tablets should be swallowed whole and should not be split before swallowing.

When alogliptin is administered in fixed combination with pioglitazone, the combination should be administered once daily without regard to meals. Fixed-combination tablets should be swallowed whole and should not be split before swallowing.

If a dose of alogliptin alone or in combination with metformin or pioglitazone is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.

Alogliptin and its metformin- or pioglitazone-containing combination products should be stored at 25degreesC (excursions permitted to 15-30degreesC). Keep alogliptin/metformin hydrochloride fixed-combination tablets in a tightly closed container. Keep alogliptin/pioglitazone fixed-combination tablets in a tightly closed container and protect from moisture and humidity.

Alogliptin is principally renally excreted; cytochrome P-450 (CYP)-related metabolism is negligible.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

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

Dipeptidyl Peptidase-Iv Inhibitors/Ace Inhibitors

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

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV). DPP-IV inhibitors can inhibit both bradykinin and substance P metabolism.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1-3)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor. Consider switching the patient to an angiotensin receptor blocker or a different anti-diabetic medication. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A pre-marketing surveillance compared incidence of angioedema in patients on vildagliptin versus a comparator. In all patients combined regardless of ACE inhibitor therapy, there was no association between vildagliptin and angioedema. However among patients taking an ACE inhibitor, vildagliptin was associated with an increased risk of angioedema (odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57 (95% CI 1.57-13.28) in the meta-analysis). This interaction may be dose-related.(4) In a pooled analysis of data from 19 clinical trials of patients on sitagliptin versus a comparator, there was no difference in the incidence of angioedema between patients on ACE inhibitors and sitagliptin compared to patients on ACE inhibitors alone or patients not on ACE inhibitors.(5) However, events were not adjudicated and encompassed urticaria, anaphylaxis, and hypersensitivity reactions, which may have confounded the results.(6) A disproportionality analysis of the WHO pharmacovigilance database found 340,686 reports of bradykinin-mediated angioedema. Of those, 345 reports involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a reporting odds ratio of 42.77 (95% CI 36.93-49.53). There was no association between use of a DPP-IV inhibitor without an ACE inhibitor and angioedema.(7)

Selected Weak Cyp2d6 Inhibitors/Tamoxifen

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)

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.

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)

Weak Cyp2d6 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Weak 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 weak 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 is also taking an inhibitor of CYP3A4 and/or has hepatic impairment, 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 weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, chlorpromazine, clobazam, clomipramine, desvenlafaxine, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sarpogrelate, sertraline, vemurafenib, and venlafaxine.(3,4)

*Known serious hypersensitivity (e.g., anaphylaxis, angioedema, severe cutaneous adverse reactions) to alogliptin.

• Acute pancreatitis

• Chronic heart failure
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Hypoglycemic disorder

• Disease of liver
• Kidney disease with likely reduction in glomerular filtration rate (GFr)

Most common adverse reactions (incidence >=4%) in patients receiving alogliptin monotherapy include nasopharyngitis, headache, and upper respiratory tract infection.

Most common adverse reactions (incidence >=4%) in patients receiving alogliptin in combination with metformin include upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain, and urinary tract infection.

Most common adverse reactions (incidence >=4%) in patients receiving alogliptin in combination with pioglitazone include nasopharyngitis, back pain, and upper respiratory tract infection.

Less Frequent

• Heart failure
• Kidney disease with reduction in glomerular filtration rate (GFr)

Rare or Very Rare

• Abnormal hepatic function tests
• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Bullous pemphigoid
• Hepatic failure
• Hypersensitivity drug reaction
• Ileus
• Rhabdomyolysis
• Skin rash
• Stevens-johnson syndrome

More Frequent

• Headache disorder
• Pharyngitis
• Upper respiratory infection

Less Frequent

• Interstitial nephritis

Rare or Very Rare

• Arthralgia
• Constipation
• Diarrhea
• Hypoglycemic disorder
• Nausea
• Urticaria

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Safety and efficacy of alogliptin alone, in fixed combination with metformin, or in fixed combination with pioglitazone have not been established in pediatric patients. Effectiveness of alogliptin monotherapy was not demonstrated in a 52-week, randomized, double-blind, placebo-controlled trial in 151 pediatric patients 10--17 years of age with inadequately controlled type 2 diabetes mellitus.

There is insufficient evidence with alogliptin in pregnant women to determine a drug-associated risk of major birth defects or miscarriage. No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180- and 149-times the 25 mg clinical dose, respectively, based on plasma drug exposure.

There is no information regarding the presence of alogliptin in human milk, the effects on the breast-fed infant, or the effects on milk production. Alogliptin is distributed into milk in lactating rats. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for alogliptin and any potential adverse effects on the breast-fed infant from alogliptin or from the underlying maternal condition.

No dosage adjustment is necessary based on age.

Of 9052 patients in clinical trials of alogliptin, 24.9% were 65 years of age and older; 4.3% were 75 years of age and older. No substantial differences in safety and efficacy relative to younger adults were observed.