Tolvaptan oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations containing tolvaptan.
Drugs List
Therapeutic Indications
Uses
Autosomal dominant polycystic kidney disease (ADPKD)
Hyponatraemia due to syndrome of inappropriate ADH secretion (SIADH)
Treatment of adult patients with hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Treatment to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease stage 1 to 4 at initiation of treatment with evidence of rapidly progressing disease.
Dosage
Adults
Hyponatraemia due to syndrome of inappropriate ADH secretion (SIADH)
Initial dose: 15mg once daily.
The dose may be increased to a maximum of 60mg once daily as tolerated to achieve the desired level of serum sodium.
Autosomal dominant polycystic kidney disease (ADPKD)
Initial dose: 60mg daily as a split dose regimen of 45mg and 15mg.
First dose: 45mg at least 30 minutes before the morning meal.
Second dose: 15mg taken 8 hours after the first dose (with or without food).
Dose titration
Titrate upward to 90mg daily (split dose of 60mg and 30mg) and then to a target of 120mg daily (split dose of 90mg and 30mg), if tolerated, with at least weekly intervals between titrations.
Additional Dosage Information
Hyponatraemia due to syndrome of inappropriate ADH secretion (SIADH)
In patients at risk of overly rapid correction of sodium (e.g. oncological, low baseline serum sodium, taking diuretics or sodium supplements) consider a dose of 7.5mg daily.
Autosomal dominant polycystic kidney disease (ADPKD)
Dose adjustments for patients taking CYP3A inhibitors
Strong inhibitors
120mg daily (split dose of 90mg and 30mg) should be reduced to 30mg once daily regimen.
90mg daily (split dose of 60mg and 30mg) should be reduced to 30mg once daily regimen.
60mg daily (split dose of 45mg and 15mg) should be reduced to 15mg once daily regimen.
Further reduction to 15mg once daily may be considered if 30mg once daily is not well tolerated.
Moderate inhibitors
120mg daily (split dose of 90mg and 30mg) should be reduced to 60mg daily (45mg and 15mg split-dose regimen).
90mg daily (split dose of 60mg and 30mg) should be reduced to 45mg daily (30mg and 15mg split-dose regimen).
60mg daily (split dose of 45mg and 15mg) should be reduced to 30mg (15mg and 15mg split-dose regimen).
Further reductions may be considered if reduced doses are not well tolerated.
Contraindications
Children under 18 years
Anuria
Breastfeeding
Galactosaemia
Hypernatraemia
Pregnancy
Serum transaminases > 3 x ULN & bilirubin >2 x ULN - if treating ADPKD
Serum transaminases > 3 x ULN & signs of toxicity - if treating ADPKD
Serum transaminases > 8 x ULN - if treating ADPKD
Precautions and Warnings
Benign prostatic hyperplasia
Diabetes mellitus
Glucose-galactose malabsorption syndrome
Lactose intolerance
Severe hepatic impairment
Severe renal impairment
Urinary obstruction
Not suitable for patients with impaired perception of thirst
Advise ability to drive/operate machinery may be affected by side effects
Exclude hypovolaemic hyponatraemia before commencing treatment
Exclude pseudohyponatraemia in diabetics with high glucose concentration
Exclude volume depletion before commencing treatment
Not all available brands are licensed for all indications
SIADH: Not to be used in urgent need to raise serum sodium acutely
SIADH: Reduce dose in patients at risk of overly rapid correction of sodium
Treatment to be initiated and supervised by a specialist
Contains lactose
Ensure patient has adequate fluid intake
ADPKD: Evaluate uric acid levels before treatment and as indicated
ADPKD: Monitor electrolytes at least every 3 months in long term therapy
ADPKD: Monitor LFTs at baseline, monthly for 18 months, then every 3 months
Monitor fluid and electrolyte status
Monitor hydration status
Monitor liver function if anorexia,nausea,vomiting,abdominal pain develop
Monitor liver function if fatigue or dark urine occurs
Monitor patient closely during titration of dose
SIADH: Monitor serum Na+ and volume at least 6 hourly until dose stabilised
ADPKD: Discontinue if chronic kidney disease (CKD) stage 5 occurs
ADPKD: Discontinue permanently if ALT/AST > 3 x ULN & bilirubin > 2 x ULN
ADPKD: Discontinue permanently if ALT/AST > 3 x ULN and INR > 1.5
ADPKD: Discontinue permanently if ALT/AST > 5 x ULN for more than 2 weeks
ADPKD: Discontinue permanently if ALT/AST > 8 x ULN
ADPKD: Discontinue permanently if ALT/AST >3x ULN & signs of hepatotoxicity
Consider dose reduction or interrupting treatment if dehydration occurs
Discontinue if serious allergic or anaphylactic reaction occurs
Discontinue in liver dysfunction; only restart after clinical evaluation
Hyponatraemia: discontinue if rapid rise in serum sodium (>12mmol/l/24hrs)
Advise patient not to take St John's wort concurrently
Grapefruit juice should not be taken simultaneously
Female: Ensure adequate contraception during treatment
Hyponatraemia due to syndrome of inappropriate ADH secretion (SIADH)
Too rapid correction of sodium can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. The rate of sodium correction should be very carefully managed in patients at risk for demyelination syndromes (e.g. hypoxia, alcoholism, malnutrition), as it may be lower than that in patients without risk factors.
In order to minimise the risk of too rapid correction of hyponatraemia the increase of serum sodium should be less than 10 to 12mmol/L/24 hours and less than 18mmol/L/48 hours.
If sodium correction exceeds 6mmol/L during the first 6 hours of administration or 8mmol/L during the first 6 to 12 hours, the possibility that serum sodium correction may be overly rapid should be considered. More frequent monitoring is advised and administration of hypotonic fluid should be considered.
In case of increases in serum sodium of higher than or equal to 12mmol/L within 24 hours or higher than or equal to 18mmol/L within 48 hours, treatment with tolvaptan should be discontinued and administration of hypotonic fluid should be considered.
Treatment of autosomal dominant polycystic kidney disease (ADPKD)
At the onset of symptoms or signs consistent with hepatic injury or if abnormal hepatic transaminase increases are detected treatment should be interrupted and repeat tests including alanine and aspartate aminotransferases (ALT and AST), bilirubin and alkaline phosphatase must be obtained as soon as possible (ideally within 48 to 72 hours). Testing must continue at increased time frequency until symptoms, signs or laboratory abnormalities stabilise or resolve, at which point tolvaptan may be reinitiated. If ALT and AST levels remain below 3 times the upper limit of normal, then tolvaptan may be cautiously continued, with frequent monitoring at the same or lower dose, as transaminase levels appear to stabilise during continued therapy in some patients.
Liver injury induced by tolvaptan has been shown in clinical trials and in post-marketing experience, acute liver failure requiring liver transplantation has also been reported.
Accurate monitoring of body weight is recommended as a progressive reduction in body weight could indicate early signs of progressive dehydration.
Pregnancy and Lactation
Pregnancy
Tolvaptan is contraindicated during pregnancy.
The manufacturer does not recommend the use of tolvaptan during pregnancy.
There is limited published information regarding the use of tolvaptan in pregnancy. Animal studies have shown reproductive toxicity.
Briggs (2015) states that although human pregnancy experience is needed for a better risk assessment, there does not appear to be a reason to withhold the drug in pregnancy if indicated.
Lactation
Tolvaptan is contraindicated during breastfeeding.
The manufacturer does not recommend the use of tolvaptan during breastfeeding.
It is unknown whether tolvaptan is excreted in human breast milk. Studies in rats have shown excretion of tolvaptan in breast milk.
High plasma protein binding should limit the amount of tolvaptan excreted into breast milk, however the effect of an exposure is unknown (Briggs, 2015).
Counselling
Advise patient not to take St John's wort concurrently.
Advise patient ability to drive and operate machinery may be affected by side effects of the treatment.
Advise patient not to take grapefruit juice simultaneously.
Ensure patient has adequate fluid intake.
Advise patient to drink fluids at the first signs of thirst.
Advise female patients adequate contraception is required during treatment.
Treatment of autosomal dominant polycystic kidney disease
Patients should be advised to drink 1 to 2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia.
Side Effects
Abdominal distension
Abdominal pain
Acute hepatic failure
Alanine aminotransferase increased
Altered liver function tests
Anaphylactic shock
Arthralgia
Aspartate aminotransferase increased
Asthenia
Constipation
Decreased appetite
Dehydration
Diarrhoea
Dizziness
Dry mouth
Dry skin
Dysgeusia
Dyspepsia
Dyspnoea
Ecchymosis
Fatigue
Gastroesophageal reflux disease
Gout
Haematuria
Headache
Hyperglycaemia
Hyperkalaemia
Hypernatraemia
Hyperuricaemia
Hypoglycaemia
Increase in serum transaminases
Insomnia
Liver damage
Malaise
Muscle spasm
Myalgia
Nausea
Neurological effects
Nocturia
Orthostatic hypotension
Palpitations
Pollakiuria
Polydipsia
Polyuria
Pruritic rash
Pruritus
Pyrexia
Rash
Renal impairment
Serum bilirubin increased
Serum creatinine increased
Syncope
Thirst
Urticaria
Weight gain
Weight loss
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: March 2021
Reference Sources
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Jinarc 15 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised February 2022.
Summary of Product Characteristics: Jinarc 30 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised April 2020.
Summary of Product Characteristics: Jinarc 45 mg and Jinarc 15 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised April 2020.
Summary of Product Characteristics: Jinarc 60 mg and Jinarc 30 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised April 2020.
Summary of Product Characteristics: Jinarc 90 mg and Jinarc 30 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised April 2020.
Summary of Product Characteristics: Samsca 7.5mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised December 2020.
Summary of Product Characteristics: Samsca 15 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised December 2020.
Summary of Product Characteristics: Samsca 30 mg tablets. Otsuka Pharmaceuticals (UK) Ltd. Revised December 2020.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 11 March 2021
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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