Xultophy PI Flashcards
What are the contents of Xultophy?
Degludec 100/3.6 of Liraglutide
When was Xultophy approved by the FDA/
2016
What are the 2 topics of the boxed warning?
1) Thyroid C cell tumors caused in rodents. Unknown if Xultophy causes thyroid C cell tumors or MTC in humans.
2) Xultophy CONTRAINDICATED in pts with personal or family history of MTC or MEN 2.
Counsel pts on potential risks of MTC & s/s thyroid tumors.
What is the indication for Xultophy?
Adjunct to diet and exercise.
Improve glycemic control of pts T2 DM adults:
1)inadequately controlled less than 50 units/day basal insulin or
2)Liraglutide 1.8mg
What are the 5 limitation for Xultophy use?
1) not recommended as 1st line therapy for pts not controlled w/diet & exercise
2) has not been studied in pts w/pancreatitis; if pt has hx pancreatitis, use something else
3) not recommended in combo with Lira or other GLP-1 RA
4) not for treatment T1DM or ketoacidosis
5) has not been studied with prandial insulin
DOSAGE & ADMINISTRATION:
What if pt is on Lira (or other GLP-1RA) & basal insulin prior to X initiation?
DC both before starting Xultophy
What is the recommended starting dose of Xultophy?
16 units - dosed per degludec = starting dose:
16 units degludec = 0.58mg of liraglutide
Dose daily SQ
What time of day is best to administer Xultophy?
Once daily same time each day
Does Xultophy has to be given with food?
Xultophy can be given with or without food.
What is the maximum daily dose of Xultophy?
Degludec 50mg + Liraglutide 1.8mg
What is the range of Xultophy which can be delivered from the pen?
Xultophy can deliver doses from 10-50 units (degludec) with each injection.
How much Liraglutide is contained in 1 unit of degludec?
Lira = 0.036mg per 1 unit Degludec
When should alternative antidiabetic products be used when Xultophy reaches what doses?
1) deg doses persistently below 16 units/day or
2) deg doses over 50 units/day
What 3 areas does PI suggest Degludec be injected?
Thigh
Upper arm
Abdomen
What are the dosage forms and strengths of Xultophy?
Injection - SQ, given once daily
Deg 100units + 1.8 mg Liraglutide in 3ml SINGLE PT use
What are the 3 contra-indications for Xultophy use?
1) pts with personal/family hx of medullary thyroid CA or pts with MEN 2
2) pts with prior, serious hyper-sensitivity rxn to Xultophy, its components or excipients
3) during episodes of hypoglycemia
Warnings & Precautions - 10
1) Thyroid C cell tumors - see boxed warning
2) Pancreatitis - post marketing reports: fatal & non-fatal hemorrhagic or necrotizing pancreatitis have been reported w/lira. DC if pancreatitis suspected.
3) Never share pen between pts - even if needle changed
4) Hyper or Hypo with changes in Xultophy regimen: close medical supervision and increase frequency of bld glucose monitoring.
5) overdose due to medication errors: a)have pt check label to avoid mix up with insulin pens; b) do not exceed max dose (50/1.8); do not give addn GLP-1RA products w/Xultophy.
Warnings and Precautions cont (6-10)
6) hypoglycemia - may be life-threatening. Increase monitoring with changes to: a) dose; b) co-admin of glucose lowering agents; c) meal pattern; d) physical activity; e) renal impairment or hypoglycemia unawareness.
7) Acute Kidney Injury -has been reported post-marketing, assoc with N/V/diarrhea/dehydration- may require hemodialysis. Advise pts of risk of dehydration due to GI ADRs; pts should avoid fluid depletion.
Hypersensitivity and Allergic Rxns:
Severe, life threatening generalized allergy, anaphylaxis, angioedema, brochospasm, hypotension, shock can occur. What is the recommendation if a hypersensitivity occurs?
Discontinue medication and tx per standard of care.
What is the recommendation for hypokalemia?
May be life-threatening.
Monitor K levels for pts at risk, treat if needed.
Fluid retention and CHF with use of TZDs.
What is the recommendation?
Observe pt for s/s heart failure. Consider decreasing dose orDC if HF occurs.
Macrovascular outcomes:
What do these studies report with Xultophy use?
No studies estab conclusive evidence of macrovascular risk reduction with Xultophy.
Adverse Rxns:
List most common SE (7) seen with Xultophy use. (In > 5% pts)
1) nasopharyngitis
2) HA
3) N
4) V
5) diarrhea
6) increased lipase
7) URI
List the 3 drug interactions:
1) drugs affecting glucose metabolism
2) anti-adrenergic drugs (beta blockers, clonidine, guanethidine, reserpine)
3) may have hypoglycemic unawareness
What are the effects of delayed Gastric Emptying on oral meds?
May impact absorption of concomitantly admin oral meds.
Can Xultophy be used in pregnancy?
Only if potential benefit justifies potential risk to fetus.
How do you titration Xultophy?
After beginning dose of 16 units, titration up or down by 2 units every 3-4 days.
What if pts need less than 16 units?
May use less than 16 units to start, however, if dose continues to be 16 units or less, DC Xultophy and use another agent.
When should you consider changing the dose of Xultophy?
To avoid hyper or hypoglycemia may change dose Xultophy:
1) changes physical activity, meals
2) changes renal/hepatic function
3) acute illness
4) use with other meds
What is the recommended titration schedule for Xultophy and how often should doses be modified?
2-0-2
Every 3-4 days modify
What is the recommendation if a dose is missed?
1) tell pts to resume dose at next scheduled time
2) do not take extra doses or increase dose to make up
3) if more than 3 days have passed since last dose - restart dose at 16 units again. (to avoid GI upse)
What is the appearance of Xultophy in the pen ?
Clear and colorless
Can the dose of Xultophy be split?
No
Since cases of MTC have been reported in pts treated with Lira postmarketing, has a causal relationship between MTC and Lira use in humans been supported?
Data have been insufficient to establish or exclude a causal relationship between MTC & Lira use in humans.
What are some of the listed s/s of thyroid tumors?
1) mass in the neck
2) dysphagia
3) dyspnea
4) persistent hoarseness
Is routine monitoring of calcitonin or using thyroid ultrasound recommended in PI to detect MTC?
Routine monitoring of calcitonin - uncertain use for early detection of MTC and may increase risk of unnecessary procedures due to:
1) low specificity of serum calcitonin (alot of things can increase level)
2) high background incidence of thyroid disease
What are usual calcitonin levels found in pts with MTC?
> 50 ng/ml
Does Lira use cause pancreatitis?
Spontaneous postmarketing reports w/Lira:
1) acute pancreatitis
2) fatal & non-fatal hemorrhagic or necrotizing pancreatitis
How many cases of pancreatitis have been reported in Lira clinical trials?
1) 13 cases in Lira group
a) 9 = acute pancreatitis
b) 4 = chronic pancreatitis
* - one case w/necrosis led to death
2) 1 case in comparator group )glimepiride)
Clinical causality could not be established
In cases of reported pancreatitis in clinical trials - what were some of the other risk factors noted? (2)
History of:
1) cholelithiasis
2) alcohol abuse
If a pt develops pancreatitis and it is stopped, can Xultophy be restarted?
NO, use other agents
Why can’t Xultophy be used for multiple pts?
Risk of transmitting blood borne diseases.
Since hypoglycemia is one of the most common ADR of insulin, name some of the SE.
1) severe - seizures
2) life threatening
3) death
4) others: can impair concentration ability and reaction time (driving or operating machinery)
Acute Kidney Injury
Post marketing reports w,Lira use have included acute renal failure & worsening of chronic renal failure - may require hemodialysis. What were some of the common s/s of these pts?
Pts experienced:
1) N
2) V
3) diarrhea
4) dehydration
5) COUNSEL pts to AVOID dehydration
List the severe, life-threatening ADRs which were reported with Xultophy use.
1) anaphylaxis
2) anagioedema
3) bronchospasm
4) hypotension
5) shock
DC Xultophy & give supportive care
Can a pt be given Xultophy with a hx of angioedema?
Use caution with these pts.
Xultophy is Contra-indicated in pts have hypersensitivity rxns to deg, lira, or excipients.
Why is there a caution about hypokalemia?
All insulin products can cause shift in K from extra to intracellular space – which can lead to hypokalemia (respiratory paralysis, ventricular arrhythmia, death).
Monitor K levels in pts at risk for hypoKalemia.
Fluid retention & CHF
Does Xultophy cause fluid retention?
No, but other products can cause fluid retention if used with insulin: PPAR - gamma agonist.
1) CHF
2) decrease or DC dose of PPAR gamma
CLINICAL TRIAL EXPERIENCE - TABLE 3
n = 1881 Mean duration exposure = 33 wks Meanage 5 yo >75 yo = 2.8% 53% male 75% white 6% AA 16% Hispanic Mean BMI ~ 32 kg/m2 Mean dur DM 8.7 yr Mean baseline A1C = 8.2% Mean baseline eGFR = 88.3 ml/min/1.73m2 6.24% pts had eGFR < 60 ml/min/1.73m2
What was the greatest ADR seen?
Nasopharyngitis = 9.6%
How were events of severe hypoglycemia defined in Phase 3 clinical programs?
episode requiring assistance of another person to administer CHO, glucagon, or resuscitate
Where there any clinically important difference in risk of severe hypo between Xultophy & comparators?
No - no clinically important differences in risk of severe hypoglycemia were observed in clinical trials.
List the % of pts in each study who reported Severe Hypoglycemia. (A, B, C)
A = vs Lira (Dual III 3851) B = vs Deg (Dual II 3912 3a) C = vs Glar (Dual V 3952)
A vs Lira = severe hypo: n=291, hypo = 0.3%
B vs Deg, n= 199, hypo = 0.5%
C vs Glar, n = 278, hypo 0%
Malignancy - Victoza
What was the rate of malignancies in pooled analysis of Lira clinical trials?
Per 1000 to yrs of malignant neoplasms:
1) 10.9% Lira
2) 6.3% PCB
3) 7.2% for active comparator
Were there malignant events reported beyond 1 yr of exposure to Lira?
Yes 1) 7 malignant neoplasm events : A) 6 events in Lira pts (4 colon, 1 prostate, 1 nasopharyngeal) B) PCB = no events C) active comparator = 1 event (colon) NO CAUSALITY ESTABLISHED.
Papillary Thyroid CA - Victoza
How many cases of papillary thyroid CA in Lira pts were reported?
1) 7 cases papillary thyroid CA in Lira pts
2) 1 case in comparator group
(Equals 1.5 vs 0.5 cases per 1000 pt yrs)
(Most of papillary thyroid CA were < 1 cm diameter)
Cholelithiasis & cholecystitis - Lira (Victoza & Saxenda):
What was the incidence of each in Lira trials?
1) Choleithiasis = 0.3% in Lira & PCB groups
= 1.5% Lira. 0.6% PCB group (Saxenda)
2) Cholecystitis = 0.2% in Lira & PCB groups
= 0.5% in Lira & 0.2% PCB groups
(The Lira group pts w/above - majority required cholecystectomy)
Is there any effect on DM retinopathy with use of Xultophy?
In general, rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of DM retinopathy, & acute painful peripheral neuropathy.
Can use of Xultophy cause lipodystrophy?
Long term use of any insulin can cause lipodystrophy at sites of repeated injections, which may affect absorption.
1) Lipodystrophy - thickening of fat tissue
2) Lipoatrophy - thinning of fat tissue
Can Xultophy cause peripheral edema?
Insulin can cause sodium retention & edema, particularly if previously poor metabolic control is improved rapidly by intensified therapy.
Did Xultophy cause weight gain in clinical trials?
Use of any insulin can cause wt gain.
In Study A - 26 wks, pts converting from Lira to Xultophy had mean increase in bwt of 2 kg.
Injection site reactions -
What was the rate of injection site reactions in pts in Xultophy studies?
Site reactions in pts treated in Xultophy group = 2.6%.
Injection site rxns: Hematoma Pain Hemorrhage Erythema Nodules Swelling Discoloration Priorities Warmth Mass
