Advice

Overview for healthcare professionals

Overview for healthcare professionals

Diltiazem hydrochloride is a calcium channel blocker and vasodilator. It is licensed in the UK for oral use to treat angina and hypertension.

Regulatory status of topical diltiazem hydrochloride

Topical diltiazem hydrochloride is not currently licensed in the UK for treating chronic anal fissure (or for treating any other condition or patient group), therefore its use is unlicensed.

In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using diltiazem outside its authorised indications.

An alternative topical treatment, 0.4% glyceryl trinitrate, is licensed in the UK for the relief of pain associated with chronic anal fissure in adults (Rectogesic 4 mg/g rectal ointment, ProStrakan). It is not recommended for use in children and young people under 18 years because of a lack of data on safety and efficacy[1]. Headache is very commonly reported by people using 0.4% topical glyceryl trinitrate. Although this can be treated with analgesics such as paracetamol, headaches may be severe (frequency 1 in 5 people) and cause people to discontinue treatment. Dizziness is also commonly reported (frequency greater than 1 in 100, but less than 1 in 10)[1].

An application for a marketing authorisation (product licence) for 4% diltiazem cream for use in chronic anal fissure is in the process of submission by S.L.A. Pharma (UK) Ltd but this product is not expected to come to market until quarter 4 of 2013/14 at the earliest[2].

Evidence statements

One Cochrane systematic review (4 RCTs; assessed as up-to-date November 2011) and 5 additional RCTs (neither considered by nor excluded from the Cochrane review) provided the evidence for this summary. The studies reviewed described using either 2% topical diltiazem hydrochloride cream or ointment. For summary purposes below, both formulations are referred to as 2% topical diltiazem. They are described separately in the Evidence review: efficacy section.

  • Evidence from a Cochrane review of 4 RCTs and 2 additional RCTs found that 2% topical diltiazem had similar efficacy to topical glyceryl trinitrate in adults. One additional small RCT in children aged 0–12 years found that 2% topical diltiazem hydrochloride was more effective than 0.2% topical glyceryl trinitrate.

  • Only 1 small study included in the Cochrane review compared topical diltiazem with no treatment (in which diltiazem was superior).

  • 2% topical diltiazem has also been compared with injection of botulinum toxin (1 study: no significant difference in healing rates) and surgery (2 studies: numerically inferior healing rates with 2% topical diltiazem but statistical analysis not performed).

  • Rates of complete fissure healing associated with 2% topical diltiazem from the 5 RCTs additional to the Cochrane review varied from 43.0% to 92.9%. These studies varied in their methodologies, populations, and follow-up.

  • Limited evidence suggests that use of 2% topical diltiazem is associated with a lower risk headache than topical glyceryl trinitrate. Mild headache, perianal itching and perianal dermatitis have been reported with the use of 2% topical diltiazem.

  • No other significant short term safety issues or side effects were reported as being associated with 2% topical diltiazem (use for 3 months or less), including in the single trial conducted in children. Longer term use was not assessed.

Summary of the evidence

This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.

One Cochrane systematic review (4 RCTs; assessed as up-to-date November 2011) and 5 additional RCTs (neither considered by nor excluded from the Cochrane review) provided the evidence for this summary. The key outcomes of complete fissure healing and headache from the 5 RCTs not included in the Cochrane systematic review are summarised in table 1.

Efficacy

The Cochrane review (Nelson et al. 2012; assessed as up-to-date November 2011) included 4 RCTs that compared 2% topical diltiazem with topical glyceryl trinitrate. Studies lasted 6–8 weeks and used 0.2% glyceryl trinitrate (3 studies, n=200 participants receiving active treatment) or 0.5% glyceryl trinitrate (1 study, n=43). All 4 studies found no statistically significant difference in healing rates between the 2 treatments[3]. One of the 4 RCTs included in the Cochrane review (Shrivastava et al. 2007) also included a no-treatment group (n=30).The healing rate in the diltiazem group was statistically significantly superior to that in the no-treatment group (80% compared with 33% respectively, p=0.014)[4].

None of the 5 RCTs additional to the Cochrane review compared 2% topical diltiazem with no treatment or placebo; comparisons were made with topical glyceryl trinitrate, topical lidocaine, botulinum toxin or surgical sphincterotomy. Of these 5 trials, 1 recruited children (mean age 32 months, range 2–144 months).

Rates of complete fissure healing associated with 2% topical diltiazem from the 5 RCTs additional to the Cochrane review varied from 43.0% to 92.9%. Recurrence rates ranged from 10.4% to 65.0%. Such widespread variation may be due in part to the differences in study methods, including length of treatment, concurrent treatments (such as a high-fibre diet), time period to assess healing, healing criteria, and follow-up time to assess recurrence.

The Cochrane review found that glyceryl trinitrate was statistically significantly better than placebo in healing anal fissure (48.9% compared with 35.5% respectively, p<0.0009). It reported that late recurrence of fissure was common, in the range of 50% of those initially cured[3].

Table 1 Summary of the 5 RCTs additional to the Cochrane review

Study

Fissure healing rate

Analysis

Rate of headache

Analysis

Diltiazem

Comparator

Diltiazem

Comparator

Sanei et al. 2009 a (n=102)

66.7% (after 12 weeks treatment)

GTN: 54.9%

p=0.2

0

GTN: 58.8%

p=0.001

Abd Elhady et al. 2009 b (n=160)

80.0% (at 8 weeks, after 4–6 weeks treatment)

GTN: 90%

Surg: 95%

Bot: not reported

Not reported

5%

GTN: 15%

Not reported

Samim et al. 2012 c (n=134)

43.0% (after 12 weeks treatment)

Bot: 43%

p=0.992

0

0

—

Suvarna et al. 2012 d (n=200)

69.2% (after 6 weeks treatment)

Surg: 95.9%

Not reported

5.5%

0

p<0.0001

Cevik et al. 2012 e (n=93, children aged

0–12 years)

82.1% (8 weeks treatment)

GTN: 39.3%

p<0.001

Not assessed

Not assessed

—

92.9% (16 weeks treatment)

GTN: 82.1%

p<0.05

Not assessed

Not assessed

—

All studies were in adults unless otherwise indicated.

Abbreviations: Bot, botulinum toxin; GTN, 0.2% topical glyceryl nitrate; n, number of study participants; Surg, surgical sphincterotomy.

a Sanei B, Mahmoodieh M, Masoudpour H (2009) Comparison of topical glyceryl trinitrate with diltiazem ointment for the treatment of chronic anal fissure: a randomized clinical trial. Acta Chirurgica Belgica 109: 727–30

b Abd Elhady HM, Othman IH, Hablus MA et al. (2009) Long-term prospective randomised clinical and manometric comparison between surgical and chemical sphincterotomy for treatment of chronic anal fissure. South African Journal of Surgery 47: 112–4

c Samim M, Twigt B, Stoker L et al. (2012) Topical diltiazem cream versus botulinum toxin a for the treatment of chronic anal fissure: a double-blind randomized clinical trial. Annals of Surgery 255: 18–22

d Suvarna R, Panchami, Guruprasad RD (2012) Chemical sphicterotomy versus surgical sphicterotomy in the management of chronic fissure in ANO: A prospective, randomized trial. Journal of Clinical and Diagnostic Research 6: 1018–21

e Cevik M, Boleken ME, Koruk I et al. (2012) A prospective, randomized, double-blind study comparing the efficacy of diltiazem, glyceryl trinitrate, and lidocaine for the treatment of anal fissure in children. Pediatric Surgery International 28: 411–6

Safety

Limited evidence suggests that 2% topical diltiazem is associated with a much lower risk of severe headache than topical glyceryl trinitrate. Mild headache, perianal itching and perianal dermatitis have been reported with the use of 2% topical diltiazem.

Cost effectiveness and cost

No studies on cost effectiveness were identified. The NHS price for 2% dlitiazem cream is £73.83 per 30 g tube and the NHS price for 2% diltiazem ointment is £163.07 per 30 g tube. The licensed topical glyceryl trinitrate product, Rectogesic 4 mg/g rectal ointment, costs £34.80 per 30 g tube (costs exclude VAT and are taken from the Drug Tariff, February 2013).

In the most recent quarter for which data are available (July to September 2012), there were 5076 prescriptions for 2% diltiazem hydrochloride cream in primary care in England at a net ingredient cost of £592,505 (a mean of £116.73 per prescription). Among all the special order products prescribed in primary care in England that quarter, 2% diltiazem hydrochloride cream ranked 6th by number of prescription items and 8th by net ingredient cost[5].


[1] ProStrakan (2012) Rectogesic 4 mg/g rectal ointment summary of product characteristics

[2] SLA Pharma (UK) Ltd: personal communication November 2012

[3] Nelson RL, Thomas K, Morgan J et al. (2012) Non surgical therapy for anal fissure. Cochrane Database of Systematic Reviews issue 2: CD003431

[4] Shrivastava UK, Jain BK, Kumar P et al. (2007) A comparison of the effects of diltiazem and glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomized clinical trial. Surgery Today 37:482–5

[5] NHS Business Services Authority. (2012) Volume and cost of special order products