Taking Tolvaptan with a grain of salt. Jia (Shermaine) Ngo LMPS Pharmacy Resident October 7, 2016

Transcription

1 Taking Tolvaptan with a grain of salt Jia (Shermaine) Ngo LMPS Pharmacy Resident October 7,

2 Learning Objectives Define Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Identify at least 3 causes of SIADH Identify at least 3 treatments for SIADH Describe the evidence of using tolvaptan in the short-term treatment of hyponatremia in patients with SIADH 2

3 Meet the Patient 3

4 Patient Case: VT ID c/c HPI Allergies 60 year old Vietnamese male (160cm, 61.5kg), admitted on Sept 1, 2016 Worsening abdominal pain and difficulty urinating. Feels like he is going to have a seizure. 1 week history of: generalized pain and discomfort upset stomach, appetite urge to urinate but has difficulty urinating ( u/o) water intake over last few weeks to u/o No previous history of above symptoms NKDA 4

5 Past Medical History Tonic-Clonic Seizures x2yrs Chronic hyponatremia Hypertension Benign Prostatic Hypertrophy (BPH) (Urinary retention ~3-4 months) Medications PTA Carbamazepine 400mg PO BID x2yrs Ramipril 10mg PO once daily (started ~1 month ago) July 25, 2016: Tamsulosin 0.4mg CR PO daily x 7 days Social Hx: Pharmacare Coverage Plan C Homeless, living in Highland House (shelter) for last 6 weeks Not working due to leg injuries No alcohol, No caffeine, Smokes ½ pack daily, No recreational drugs Poor diet 5

6 Review of Systems (Sept 1, 2016) Vitals Temp 36.6 o C BP 155/97 HR 79 RR 18 O 2 Sat 99% RA CNS EENT CVS RSP GI GU/renal Liver Endo MSK Derm Alert and oriented x3 GCS 15 Dizziness when walking Has auras and feels like he is going to have a seizure Unremarkable No CP, No S3 + S4, No edema, JVP 2cm ASA, euvolemic SOB appetite, epigastric pain, abdo: soft, non-tender with BS x4 Post-void residual: 300mL of urine Foley catheter inserted Unremarkable 6

7 Serum [Na + ] Serum [K + ] Serum [Cl - ] scr Relevant Labs Sept 1, mmol/l ( from Jul, 2016: 125 and Jul, 2015: 126) 4 mmol/l 86 mmol/l 39 umol/l egfr >120 ml/min/1.73m 2 Anion Gap 14 Plasma Osmolality 249 mosm/kg (N: mosm/kg) Urine Osmolality 236 mosm/kg (N: mosm/kg) Urine Na+ 65 mmol/l (N ~ 20 mmol/l) R Glucose 4.8 mmol/l TSH 1.3 U/mL Cortisol AM 510 nmol/l LFTs WNL Carbamazepine Trough 34 umol/l (N: umol/l) 7

8 Patient Case: VT ECG (09/1): CXR (09/2): CT Head (09/2): Diagnostics Unremarkable Unremarkable Moderate cerebral and less marked cerebellar atrophy Renal CT (09/2): Enlarged prostate. A large left posterior L4-5 disc herniation also appears to be present 8

9 Current Medications Medical Conditions Tonic-Clonic Seizures Medications Carbamazepine 400mg PO twice daily Chronic hyponatremia Hypertension Benign Prostatic Hypertrophy DVT Prophylaxis Ramipril 10mg PO once daily Dalteparin 5000 units SC once daily Acetaminophen 325mg 1-2 tabs PO Q4H PRN Zopiclone 5mg PO QHS PRN Dimenhydrinate 50mg PO Q4H PRN 9

10 Drug Therapy Problems VT is experiencing loss in appetite, and is at risk of experiencing seizures, secondary to having hyponatremia induced by carbamazepine and ramipril. He would benefit from a reassessment of his therapy. VT is experiencing difficulty urinating and urinary retention, secondary to not receiving any therapy for his benign prostatic hypertrophy. He would benefit from initiation of therapy. VT is at increased risk of CHD, atherosclerotic CVD, ischemic strokes and mortality, secondary to smoking ½ pack per day. He would benefit from education regarding smoking cessation. 10

11 Background 11

12 Anti-Diuretic Hormone (ADH) a.k.a. vasopressin V2 plasma osmolality stimulates ADH release water reabsorption = plasma osmolality + urine osmolality European Journal of Endocrinology (2014) 170, G1 G47 De las Peñas R et al. Clin Trans Oncol

13 Syndrome of Inappropriate Anti-Diuretic Hormone Secretion SIADH: Disorder of impaired water excretion Sustained and inappropriate release of ADH from the posterior pituitary gland Inappropriate: ADH release occurs independently from effective serum osmolality or circulating volume Pathogenesis: ADH water retention *Na + ] volume activates 2 o natriuretic mechanisms sodium and water loss near-euvolemia European Journal of Endocrinology (2014) 170, G1 G47 De las Peñas R et al. Clin Trans Oncol

14 Syndrome of Inappropriate Anti-Diuretic Hormone Secretion Diagnosis of Exclusion Absence of adrenal, thyroid, pituitary or renal insufficiency No recent use of diuretics SIADH: Serum Na < 135 mmol/l Plasma osmolality < 275mosm/kg Urine osmolality > 100mosm/kg Urine [Na+] > 30mmol/L Clinical euvolemia VT: 121 mmol/l 249 mosm/kg 236 mosm/kg 65 mmol/l Euvolemic European Journal of Endocrinology (2014) 170, G1 G47 De las Peñas R et al. Clin Trans Oncol

15 Complications of SIADH Hyponatremia (Na` <135mmol/L): risk of mortality, morbidity and length of hospital stay CNS RESP GI MSK Headache, altered mental status, fatigue, weakness, irritability, seizures, coma, poor balance, brain damage, death Respiratory arrest Nausea, vomiting, loss in appetite Muscle cramps, tremors Profound hyponatremia (<125 mmol/l): risk of symptoms 1 European Journal of Endocrinology (2014) 170, G1 G47 Support Care Cancer (2016) 24: Am. J. Med. Vol 124, No 10, October 2011 Ther Adv Endocrinol Metab Apr; 3(2):

16 Causes of SIADH CNS Stroke, hemorrhage, inflammation, trauma Malignancies Pulmonary inflammation, infections Urinary Retention Idiopathic risk with age (>50yo) Drugs (Many!) Carbamazepine Oxcarbazepine Sodium valproate Lamotrigine Chlorpropamide SSRIs, TCAs, mirtazapine NSAIDs? Ramipril European Journal of Endocrinology (2014) 170, G1 G47 CPJ/RPC (2007). 140 (6):

17 risk of mortality Goals of Therapy risk of complications from SIADH (e.g. seizures) Minimize length of hospital stay Normalize surrogate markers (i.e. serum Na +, plasma osmolality, urine Na+, urine osmolality) Improve quality of life Minimize adverse reactions 17

18 Therapeutics Approach 1. Treat any underlying cause(s) 2. Fluid restriction ( mL/day) 3. Intravenous saline infusion 4. Oral salt tablets +/- loop diuretic 5. Urea 6. Last lines: Tolvaptan, Lithium, Demeclocycline European Journal of Endocrinology (2014) 170, G1 G47 UpToDate: Treatment of Hyponatremia Ther Adv Endocrinol Metab Apr; 3(2):

19 Team asks a question 19

20 Clinical Question P I C O 60 year old male with SIADH serum Na + : 121 mmol/l Tolvaptan 15 30, 60mg PO daily (Max: 60mg daily) Standard Care (e.g. fluid restriction) Mortality Length of hospital stay in serum Na + Quality of life 20

21 Tolvaptan OA Indications Doses Onset of action Peak effect Vasopressin receptor antagonist (VRA) affinity and selectivity in inhibiting V 2 receptor excretion of free water, urine ouput urine osmolality, serum Na+ Treatment of clinically important, non-hypovolemic hyponatremia (e.g. serum [Na + ] <130mmol/L or symptomatic hypona + ) Initial dose: 15mg PO once daily Titrate if <5mmol/L in 24 hrs and Na + <130mmol/L 30mg, 60mg PO once daily 2-4 hours 4-8 hours 21

22 Search Strategy Databases Search Terms Inclusion Results Medline, PubMed Tolvaptan AND Syndrome of Inappropriate Antidiuretic Hormone Secretion OR Hyponatremia OR Inappropriate ADH Syndrome Humans, Adults, English 2 systematic reviews/meta-analysis 4 RCTs 5 reviews 9 case reports 3 retrospective studies 1 observational studies 1 prospective studies 22

23 N Engl J Med 2006;355:

24 SALT-1 and SALT-2 Design P SALT-1 (42 sites in USA) Apr 11, 2003 to Dec 20, 2005 SALT-2 (International sites) Nov 20, 2003 to Jul 6, 2005 Multi-center, double-blinded, placebo-controlled, phase III RCT Euvolemic or hypervolemic hyponatremia (diverse causes) Includes: >18yo, hypona + associated with CHF, cirrhosis or SIADH Excludes: hypovolemic hyponatremia, head trauma, adrenal insufficiency, hyponatremia associated with meds that could be safely withdrawn, urinary tract obstruction, progressive or episodic neurologic disease I N = 102 N = 123 Tolvaptan 15mg PO once daily x 30 days ( to 30 and then to 60mg PO once daily if needed in 1 st 4 days) C N = 103 N = 120 Placebo 15mg PO once daily x 30 days ( to 30 and then to 60mg PO once daily if needed in 1 st 4 days) *Fluid restriction not mandatory* *Not allowed to use demeclocycline, lithium choride or urea* N Engl J Med 2006; 355;

25 O SALT-1 SALT-2 Primary Endpoints: in average daily AUC for serum [Na + ] from baseline to day 4 in average daily AUC for serum [Na + ] from baseline to day 30 Secondary Endpoints: in AUC for serum [Na + ] in patients with marked hyponatremia Absolute serum [Na + ] at each visit Time to normalization of the serum [Na + ] % of pts with serum [Na + ] that had normalized and the categorical serum [Na + ] on day 4 and 30 Fluid intake and output on day 1 in body weight in patients with hypervolemic hyponatremia on day 1 Fluid restriction or use of IV saline as rescue therapy from baseline in scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Medical Outcomes Study 12-item Short-Form General Health Survey 25

26 Patients Characteristics SALT-1 SALT-2 Tolvaptan Placebo Tolvaptan Placebo Age Males 50% 59% 52% 53% Race White 70% Black 13% Hispanic 13% Other 5% White 74% Black 17% Hispanic 9% Other 1% White 96% Black 1% Hispanic 2% Other 1% Euvolemic 60% 65% 51% 50% SIADH cause 41% 48% 40% 42% White 91% Black 2% Hispanic 5% Other 2% Marked hypona + 52% (53) 50% (52) 48% (59) 48% (58) Avg Na + for mild ( ) Avg Na + for marked (<130)

27 Results Efficacy Primary endpoint: change in average AUC for serum sodium mmol/l In patients with marked hyponatremia: SALT-1 SALT-2 Tolvaptan (N= 102) Placebo (N= 103) P-value Tolvaptan (N= 123) Placebo (N= 120) P-value Day < < Day < < Average absolute change in sodium (in mmol/l): Tolvaptan Placebo Day Day

28 Results Efficacy 28

29 Results Safety 29

30 Subgroup analysis: SIADH Outcomes Tolvaptan N = 51 Placebo N = 58 P-Value in average daily AUC on day 4 (mmol/l) in average daily AUC on day 30 (mmol/l) P < P < of 51 (5.9%) tolvaptan-treated pts exceeded correction limits of in Na+ > 12 mmol/l over 1 st 24 hr of correction and > 18 over the 1 st 48 hr All 3 had marked hyponatremia (Na + < 130) In combined SALT studies, no patients exhibited any neurological symptoms suggestive of osmotic demyelination syndrome Eur J Endocrinol May ; 164(5):

31 Subgroup analysis, cont. Outcomes Tolvaptan Placebo P-Value Mean hospital LOS (days) P = (NSS) in PCS Score on day P = in MCS Score on day P = Most common AEs: thirst (18%), dry mouth (16%) Deaths: tolvaptan (N=1), placebo (N=3) No deaths were considered to be treatment related 31

32 Methodology Limitations Patient population: 50-60% euvolemic, 40-50% SIADH cause Excluded patients: On meds associated with Na+ that could be safely withdrawn Urinary tract obstruction Progressive or episodic neurologic disease Fluid restriction is not mandatory Clinically?Standard therapy Primary outcome: serum [Na + ] = surrogate marker?validity of SF-12 Health Survey for Physical and Mental Component Summary Scales in patients with hyponatremia Industry sponsored 1 Am J Cardiol 2006;97:

33 Strengths: Relatively large RCT Advantages N>100 in each treatment arm (90% power) Reproducibility Gheorghiade et al. compared tolvaptan 10mg daily (up to 60mg) vs. fluid restriction + placebo x 27 days 1 N=28, in serum Na + (mmol/l): Tolvaptan: vs. Fluid restriction: Chen et al. Tolvaptan 15mg daily (up to 60mg) vs. placebo x 7 days 2 N = 45, in serum Na + (mmol/l): Tolvaptan vs. Placebo SIADH sub-group analysis 1 Am J Cardiol 2006;97: ACCP 2014; 54(12):

34 Bottom Line... tolvaptan, when added to standard therapy, was superior to placebo in raising and maintaining serum sodium concentrations in patients with euvolemic or hyper-volemic hyponatremia of diverse origin. 34

35 Meta-Analysis Am. J. Med. Vol 124, No 10, October

36 Bertrand et al Design Methods Inclusion Meta-analysis 1950 to May 2010 MEDLINE, ClinicalTrials.gov, scientific abstracts RCTs that examined efficacy of VRAs in treating hyponatremia tolvaptan, satavaptan, lixivaptan, conivaptan, relcovaptan humans no language restrictions Results 11 RCTs (N = 1094) 36

37 37

38 38

39 Results Efficacy 39

40 Results Safety 40

41 Bottom Line Short-term use of VRAs in treating hyponatremia was successful at raising serum [Na + ]. Additional experience is required to guide their optimal use and minimize safety concerns. serum *Na + ] by 3-5 mmol/l relative to placebo over 4 days. 41

42 Summary Tolvaptan: efficacy in serum Na+ Eur J Endocrinol Guidelines (2014): No significant reduction in death 60% higher chance of rapid in serum *Na + ] 26 per 1000 treated patients Samsca (Mar 2012): reports of neurological sequelae in patients treated with tolvaptan Advise: close monitoring of serum sodium, especially in patients with Na + <120mmol/L 42

43 risk of mortality Goals of Therapy risk of complications from SIADH (e.g. seizures) Minimize Length of Hospital Stay Normalize surrogate markers (i.e. serum Na +, plasma osmolality, urine Na+, urine osmolality) Improve quality of life Minimize adverse reactions 43

44 Efficacy: serum *Na + ] Tolvaptan in VT?Reduce risk of seizures, death and hospital stay Safety: Risk of osmotic demyelination syndrome Adherence: Severity linked to rate of correction Most crucial in day 1 and 2 of correction Na + <120mmol/L and chronic hyponatremia Important Limitations: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA Costs: $90.41 per tablet Non-Pharmacare benefit + No Special Authority + Non-Formulary 44

45 Therapeutic Options Alternatives Pros Cons Fluid restriction ( mL/day) Saline infusion Salt tablets +/- oral diuretics Initially serum Na + Prevents further serum Na + Inexpensive Relatively reliable correction Most useful in euvolemic hypona+ with serious s/s Generally effective Rapid onset Poor compliance As sole tx, unlikely to correct hyponatremia Risk of ODS Careful monitoring required Nausea, vomiting Electrolyte imbalance Urea Onset immediate Unpleasant taste Demeclocycline Works in ~60-70% of patients Nephrotoxicity No longer recommended Not available in Canada Slow onset of action (2-5 ds) Lithium Vaptans No fluid restriction (allowed to drink to thirst) Quick onset: 2-4 hours No longer recommended Neuropsychiatric side effects Slow onset of action (3-6 ds) Hepato-toxicity SEs: thirst, dry mouth, risk of ODS?Hard outcomes Costs expensive 45

46 Recommendations 1. Start Levetiracetam 500mg PO BID x 48 hours (steady state) - If well-tolerated, to 1000mg PO BID 2. After levetiracetam 1000mg PO BID x 48 hours carbamazepine to 300mg PO BID Tapering Plan: by 100mg/dose Q2 weeks as tolerated 3. Discontinue Ramipril 4. Initiate Amlodipine 5mg HS 5. Fluid restriction (< 1.5L per day) 6. NaCl tablet 500mg PO BID 7. Initiate Tamsulosin 0.4mg CR PO once daily 46

47 Monitoring Plan Efficacy Monitoring Parameters By Who? Expected? When? Serum Na + + CHEM 6 Pharmacist Physician Nurse Trend (<10 mmol/l in 1 st 24 hrs) Fluid intake <1.5 L/day Daily Urine output (N: ~738 ml) Daily Sxs: difficulty/pain urinating, general and abdominal pain Decrease or Absence Q 4 hours x 24 hours then daily if improving Daily Tonic Clonic Seizures Absence Daily Blood Pressure < 140/90 Daily 47

48 Monitoring Plan Safety Monitoring Parameters By Who? Expected? When? CNS HEENT CVS Seizures, lethargy, mental status exam (for depression, irritability), ataxia Eye exam (for nystagmus), vision changes (double vision), dysphagia, Orthostatic hypotension, peripheral edema Pharmacist Physician Nurse Presence Presence Presence (HR >30bpm, SBP < 20mmHg from lying sitting) GI Appetite Decrease Renal egfr, scr Stable Derm Skin tenderness, blistering, exanthematous eruption Presence Anytime Daily in hospital 48

49 What happened 1. Start Levetiracetam 500mg PO BID 2. Continued carbamazepine 400mg PO BID Plan: cross-taper as out-patient with neurology clinic 3. Discontinue Ramipril 4. Initiate Amlodipine 5mg HS 5. Fluid restriction (< 1.5L per day) 6. NaCl tablet 500mg PO BID 7. TURP scheduled on Sun, Sept 4 49

50 Follow-Up Sept 1: Hospital Admission NaCl 500mg PO BID Fluid restriction <1.5L/day Na u/o: 825 ml Urine osmol: 236 Urine Na: 65 BP 155/97 Sept 2: Na u/o: 850mL Asymptomatic BP 130/78 Sept 4: Transurethral resection of prostate Na u/o: 900 ml Asymptomatic BP 138/92 Sept 9: 1 day after discontinuation of foley catheter Na voiding well Urine osmol: 129 Urine Na: 32 Asymptomatic BP 125/93

51 Thank you! Questions? 51