New drugs for hyponatraemia

In the Editorial "New Drugs for Hyponatraemia"(1), we found several
points which would deserve detailed discussion and challenge, such as the
robustness of the available evidence and the discrepancy in approved
indications in US and Europe for tolvaptan. For these, we prefer to
reiterate that the tolvaptan registration dossier containing all available
dataset on its efficacy, safety and quality has led to the granting of
marketing authorisation in the US, Europe and recently, Japan.

Inconsistencies of approved indications across the globe are not uncommon,
especially for newly introduced classes of drugs. This remains a
challenge for the pharmaceutical industry as a whole, when data is
generated to satisfy different regulatory requirements in different
Regions.

We feel obliged to comment in more detail on two points raised by the
Authors: the safe use of vasopressin 2 receptor antagonist and the
effectiveness of the available therapeutic options for hyponatraemia.

Rapid correction of hyponatraemia is a well known risk that needs to be
considered regardless of the chosen therapeutic option. The tolvaptan
prescribing information(2) states that patients should be monitored for
serum sodium and volume status and that treatment should be initiated in
hospital. The prescribing information goes further, by recommending
discontinuation of tolvaptan in patients who develop too rapid a rise in
serum sodium (>12 mmol/l per 24 hours). Tolvaptan is available as 15mg
and 30mg tablets and careful titration, starting from 15mg once daily, may
facilitate monitoring of therapeutic effect on fluid and electrolyte
balance. In common with other treatments for euvolaemic and hypervolaemic
hyponatraemia, vasopressin 2 receptor antagonists should not be used in
situations where both water and sodium levels are low. Indeed,
hypovolaemic hyponatraemia is a listed contraindication in the tolvaptan
prescribing information. Finally, tolvaptan has not been studied in a
setting of urgent need to raise serum sodium acutely. For such patients,
alternative treatment should be considered.

We were surprised with the apparent level of satisfaction about existing
therapeutic options expressed by the Authors. This is in contrast with
the feedback we received from Investigators participating in the tolvaptan
clinical development programme and from market research involving over
1,000 hospital physicians across Europe.

Fluid restriction is a commonly used treatment for asymptomatic
hyponatraemia. The required amount of restriction ultimately depends on
the degree of diluting impairment present in the individual patient, but,
in general, restriction to 1000 mL/day may gradually achieve negative
water balance and an increase in serum sodium concentration. From a
practical perspective, severe water restriction is difficult to enforce
for prolonged periods. Therefore, for many patients, long-term fluid
restriction can be uncomfortable, difficult to maintain, and relatively
ineffective(3).

Demeclocycline is a tetracycline derivative which inhibits the
antidiuretic effect of AVP on the renal tubules and increases the
excretion of solute-free urine. However, it has been associated with a
slow onset of action and risk of nephrotoxicity(4). Demeclocycline is
contraindicated in hepatic impairment and renal impairment, due to
reported drug-induced renal failure related to use in cirrhotic patients(5
-8). The initial dose of 900-1200mg (6-8 150mg tablets) in divided doses
requires reduction to a maintenance dose of 600mg (4 150mg tablets) after
8-10 days to reduce the risk of nephrotoxicity(9). Demeclocycline is not
FDA approved for use in hyponatraemia in the US; in Europe it is only
licensed in the UK and France, where the indication is treatment of SIADH
particularly of paraneoplasic origin, with chronic hyponatraemia <125
mmol/L and/or associated clinical signs related to hyponatraemia and
resistant to fluid restriction.

A letter to the BMJ does not seem to us the appropriate place for a debate
on tolvaptan cost. The Authors have expressed their opinion of what
constitutes an "expensive" treatment option. We believe that factors in
addition to absolute cost, such as cost-effectiveness, resource
utilisation and overall budget impact should also be taken into
consideration.

We agree with the Authors that the appropriate place of vasopressin 2
antagonists within the therapeutic options for hyponatraemia remains to be
further defined. As for all new classes of drugs, this will be fully
understood only when the available evidence from clinical development is
transferred to years of experience in daily medical practice.

References

1. Amin A and Meeran K. New drugs for hyponatraemia. BMJ 2010; 341: c6219.

2. Samsca SmPC.

3. Wong LL and Verbalis JG. Vasopressin V2 receptor antagonists.
Cardiovasc Res 2001; 51: 391-402.

4. Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and
nephrotoxicity. Correlation in hyponatremic cirrhotic patients. JAMA 1980;
243: 2513--5.

5. Carrilho F, Bosch J, Arroyo V. Renal failure associated with
demeclocycline in cirrhosis. Ann Intern Med 1977: 87: 195-7.

6. Curtis NJ, van Heyningen C, Turner JJ. Irreversible nephrotoxicity from
demeclocycline in the treatment of hyponatremia. Age and Ageing 2002; 31:
151-2.

7. Roth H, Becker KL, Shalhoub RJ, Katz S. Nephrotoxicity of
demethylchlortetracycline hydrochloride. A prospective study. Arch Intern
Med 1967; 120: 433-5.

8. Padfield PL, Morton JJ, Hodsman GP. Demeclocycline in the treatment of
the syndrome of inappropriate antidiuretic hormone release: with
measurement of plasma ADH. Postgrad Med J 1978; 54: 623-7.

9. Prescribing Information (US, Declomycin Glades Pharmaceuticals; EU,
Alkonatrem Genopharm).