Macrogol

Movicol
Macrogol 3350, sachet containing 13.125 g powder, 30, Movicol; sachet containing 6.563 g powder, 30, Movicol-Half

Purpose of Application

To seek the following:

a. an extension to the current listing to include the treatment of faecal impaction in adults, where conventional therapies have failed, and the alternative treatments may require hospitalisation; and

b. a similar listing for a lower strength product that can be used in adults and children for the treatment of faecal impaction, where conventional therapies have failed, and the alternative treatments may require hospitalisation.

Background

At the June 2002 PBAC meeting, Macrogol 3350 (13.125 g, sachet) was recommended for a restricted benefit listing for the treatment of constipation in patients with malignant neoplasia, on the basis of acceptable cost-effectiveness compared to lactulose. PBS listing was implemented on 1 November 2002.

Registration Status

Movicol is TGA approved for the following indications:

• treatment of constipation.
• faecal impaction, defined as refractory constipation with faecal loading of the rectum and/or colon confirmed by physical examination of abdomen and rectum.

Movicol-Half is TGA approved for the following indications:

• effective relief from chronic constipation in adults and children over 12 years.
• resolving faecal impaction in adults and children. Faecal impaction is defined as refractory constipation with faecal loading of the rectum and/or colon confirmed by physical examination of abdomen and rectum.

Listing Requested and PBAC’s View

Restricted benefit

The treatment of faecal impaction, where conventional therapies have failed, and alternative treatments may require hospital admission.

Clinical Place for the Proposed Therapy

Macrogol 3350 with electrolytes provides an alternative treatment for faecal impaction in adults and children aged 2 years and over. Current treatment for faecal impaction in adults and children includes repeat enemas and suppositories or large volumes of lavage solution or manual disimpaction requiring hospitalisation.

Clinical Claim

The submission described Movicol and Movicol-Half as having similar effectiveness to conventional therapy, but with less toxicity.

Economic Analysis

No formal economic evaluation was included in the submission. The economic case presented assumed a 90% effectiveness rate for adults and children for Movicol and Movicol-Half

Recommendation and Reasons

The PBAC considered there was potential for the inappropriate use of Movicol and Movicol -Half if they were listed as a restricted benefit as requested. This potential for widespread usage arises for several reasons, including that faecal impaction and severe constipation are similar conditions of differing severity (two of the studies presented investigated both conditions) and variations may therefore exist among clinicians in differentially diagnosing between them.

The PBAC noted the choice of comparator implicitly assumed hospitalisation alone, however, other oral laxatives: are employed outside hospital and are more commonly used than manual disimpaction; are in a similar therapeutic class as Movicol; and are in liquid formulation similar to reconstituted Movicol. Further, faecal impaction may be treated in outpatients’ departments without requiring inpatient admission.

The PBAC did not accept that the evidence based solely on single-arm, open-label studies is adequate to support the comparative effectiveness of Movicol and Movicol-Half in the treatment of faecal impaction against other alternative interventions for PBS listing. Overall, the PBAC considered the measures taken by investigators to minimise bias in the studies were inadequate.

All key studies presented were single-arm, open-label studies with small sample size and short duration. The PBAC noted comparisons across these studies were potentially subject to important sources of bias such as selection and observer bias because there were no randomisation, blinding or comparative arm. The assessment of the patient-relevant outcomes was considered by the PBAC to be highly subjective; often based on patient’s self-report.

All four studies enrolled patients who had previously used laxatives in an attempt to resolve faecal impaction/severe constipation prior to study commencement. In the absence of a comparative arm, the PBAC considered that it is difficult to differentiate the effects of Movicol from previous laxatives and it was also uncertain whether the reported adverse events can be attributed to Movicol or faecal impaction.

Nevertheless, the PBAC considered there is clinical place for Movicol and Movicol-Half in the treatment of chronic constipation not responding to conventional therapies. However, evidence demonstrating comparative effectiveness in this patient group had not been presented.

There was no formal economic evaluation included in the submission, and the PBAC agreed the assumptions on which the estimates for the costs to the PBS and offsets to government health budgets were based were poorly justified. The PBAC also noted that because all key studies are single-arm, open-label studies, the results of any economic evaluation, if performed, would be difficult to interpret. In the absence of any clinical data to suggest Movicol and Movicol-Half are more effective than paraffin oil or lavage solutions of polyethylene glycol (PEG), any off-sets to the budgets of public hospital (and hence state and territory government) budgets based on an assumption that Movicol and Movicol-Half could further reduce hospitalisations was likely to be overestimated. Further the extent to which these claimed reduced hospitalisation episodes are realised as financial savings to government health budgets was not discussed and was also a source of overestimation.

The PBAC did not accept data from the AIHW National Hospital Morbidity Database on hospital separations for constipation as a measure of the extent of, and costs associated with, hospitalisation for faecal impaction. In particular, patients with other co-morbidities may be hospitalised anyway.

Therefore, the PBAC rejected the submission because clinical and economic uncertainties and inadequately demonstrated cost-effectiveness.

Context for Decision

The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.

Sponsor’s Comment

The sponsor wishes to note that whilst other oral laxatives may be more commonly used than manual disimpaction for the treatment of faecal impaction, none of these treatments are approved by the Therapeutic Goods Administration (TGA) for use for this purpose.

Flow chart for the treatment of functional constipation and faecal impaction

Clinicians can choose to enter the pathway at any stage depending on the history, severity of the symptoms and compliance to medication.

Movicol-Half
Macrogol 3350 plus electrolytes

Presentation

Movicol-Half is a free following white powder. Each sachet of Movicol-Half contains:

Macrogol 3350 6.563 g
Sodium chloride 175.4 mg
Sodium bicarbonate 89.3 mg
Potassium chloride 23.3 mg

Movicol-Half also contains a lime and lemon flavour and potassium acesulfame as a sweetener.

The content of electrolyte ions per sachet when made up with 62.5 mL of water is:

Sodium 65 mmol/L
Potassium 5.4 mmol/L
Chloride 53 mmol/L
Bicarbonate 17 mmol/L

Uses Actions

ATC code: A06A D

Macrogol 3350 exerts an osmotic action in the gut, which induces a laxative effect. Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular pathways. The physiological consequence is an improved propulsive colonic transportation of the softened stools and a facilitation of the defaecation. Electrolytes combined with macrogol 3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal water without net gain or loss of sodium, potassium and water.

The laxative action of macrogol has a time course which will vary according to the severity of the constipation being treated. Faecal Impaction – In a non-comparative study in 27 adult patients, Movicol cleared the faecal impaction in 12/27 (44%) after 1 day’s treatment, 23/27 (85%) after 2 day’s treatment and 24/27 (89%) at the end of 3 days.

In a non-comparative study in 63 children, Movicol cleared the faecal impaction in 92% of patients within 3-7 days of treatment (median 6 days). For the 2-4 years age group, the average total number of sachets required was equivalent to 28.6 Movicol-Half sachets, and for the 5-11 age group the average total number of sachets was equivalent to 47.2 Movicol-Half sachets.

Pharmacokinetics

Macrogol 3350 is unchanged along the gut. It is virtually unabsorbed from the gastrointestinal tract and has no known pharmacological activity. Any macrogol 3350 that is absorbed is excreted via the urine.

Indications

For effective relief of constipation in adults. For treatment of chronic constipation in adults and children aged 2 years and older. For resolving faecal impaction, defined as refractory constipation with faecal loading of the rectum, or the rectum and colon, confirmed by physical examination of abdomen and rectum, in adults and children aged 2 years and older. For prevention of recurrence of faecal impaction in children aged 2 years and older. Use in children aged 2 years and older should be limited to 12 weeks except under medical supervision.

Dosage and Administration

Adults and children over 12 years:

Constipation:

The dose is 2 sachets daily and may be increased up to 6 sachets daily if required. For chronic constipation the dose may be reduced to 1 sachet daily according to individual response.

For patients of 12 years and older using 2 sachets daily or more, it is recommended to use Movicol.

Faecal Impaction:

16 sachets daily, all of which should be consumed within 6 hours. A course of treatment for faecal impaction does not normally exceed 3 days.

For patients of 12 years and older it is recommended to use Movicol.

Children 2 years and older:

Chronic constipation and prevention of recurrence of faecal impaction:

Children aged 2-5 years: The usual starting dose is 1 sachet daily.

Children 6-11 years: The usual starting dose is 2 sachets daily.

The dose should be adjusted up or down as required to produce regular soft stools. The maximum dose does not normally exceed 4 sachets a day.

Use in children aged 2 years and older should be limited to 12 weeks except under medical supervision.

Movicol-Half is not recommended for children below 2 years of age.

Faecal Impaction:

Children 2-11 years. A course of treatment for faecal impaction with Movicol-Half is for up to 7 days as follows:

	Number of Movicol-Half sachets
Age (years)	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
2-5	2	4	4	6	6	8	8
6-11	4	6	8	10	12	12	12

The above dosage regimen should be stopped once disimpaction has occurred. An indicator of disimpaction is the passage of a large volume of stools. After disimpaction, it is recommended that the child follows an appropriate bowel management programme to prevent reimpaction.

Movicol-Half is not recommended for children under 2 years of age.

Patients with impaired cardiovascular function

Adults and children over 12 years:

For the treatment of faecal impaction the dose should be divided so that no more than four sachets are taken in any one hour.

Children (2-11 years):

There are no clinical data for this group of patients, therefore Movicol-Half is not recommended for use in this patient group.

Patients with renal insufficiency

Adults and children over 12 years:

No dosage change is necessary for treatment of either constipation or faecal impaction.

Children (2-11 years):

There are no clinical data for this group of patients, therefore Movicol-Half is not recommended for use in this patient group.

Administration

For oral administration.

Each sachet should be dissolved in ¼ cup (approx 60ml) of water. For use in faecal impaction the correct number of sachets can be reconstituted in advance and kept covered and refrigerated for 24 hours. For example 12 sachets can be made up into 750ml of water and 16 sachets into one litre of water.

Contraindications

Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, ileus and severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, ulcerative colitis and toxic megacolon.

Known hypersensitivity to macrogol or any of the excipients.

Warnings and Precautions

Mild adverse reactions are possible as described under Adverse Effects. If patients develop any symptoms indicating shifts of fluid/electrolytes (eg. oedema, shortness of breath, increasing fatigue, dehydration, cardiac failure) Movicol-Half should be stopped immediately and electrolytes measured, and any abnormality should be treated appropriately.

Prolonged use is undesirable and may lead to dependence. Patients should be advised to drink plenty of water and increase fibre in the diet, except in cases of medication-induced constipation.

Mutagenicity and Carcinogenicity

Preclinical studies show that macrogol 3350 has no significant systemic toxicity potential, although no tests of its genotoxicity have been conducted.

Use in Pregnancy and Lactation

There is no experience of the use of Movicol-Half during pregnancy and lactation. No preclinical tests of its effects on reproduction have been conducted.

Movicol-Half should only be used if considered essential by the physician.

Use in Children

The safety and efficacy of Movicol-Half in the treatment of chronic constipation in children under two years of age has not been established.

Chronic constipation in children:

Constipation is the less-frequent-than-usual passage of large, firm or hard stools. Most normal children will occasionally experience constipation, which will normally require no more than a healthy diet, plenty of exercise, regular toilet use and, sometimes, occasional use of laxatives. However, a small proportion of children will pass stools less frequently than 3 times per week, with excessive straining and discomfort or pain at these times. For these children a supervised plan of treatment over a period of at least 6 – 12 months, utilising a product such as Movicol-Half, to restore normal patterns of toilet use and stool formation may be considered appropriate.

Interactions

No clinical interactions have been reported. Macrogol raises the solubility of drugs that are soluble in alcohol and relatively insoluble in water. There is, therefore, a theoretical possibility that the absorption of such drugs could be transiently reduced. A theoretical potential also exists for decreased absorption (rate and extent) of drugs which are generally poorly absorbed or are contained in sustained or modified release dosage forms. This is more likely to occur if Movicol-Half is overdosed to induce watery diarrhoea.

Overdosage

Severe pain or distention can be treated by nasogastric aspiration. Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.

Pharmaceutical Precautions

Sachet: Store below 25°C.

Solution: Store 2-8°C (in refrigerator and covered).

Medicine Classification

General Sale Medicine.

Package Quantities

Boxes of 30 sachets. Each sachet contains 6.9g of powder.

Table: Laxatives – recommended doses

Laxatives	Recommended doses
Macrogols
Movicol	Movicol Paediatric Plain (Norgine) a Oral powder, macrogol ’3350′ (polyethylene glycol ’3350′) 6.563 g, sodium bicarbonate 89.3 mg, sodium chloride 175.4 mg, potassium chloride 25.1 mg/sachet. Given by mouth.
	Disimpaction
	Child under 1 year: half to 1 sachet daily (non-BNFC recommended dose)
	Child 1-5 years: treat until impaction resolves or for maximum 7 days. Two sachets on 1st day, then 4 sachets daily for 2 days, then 6 sachets daily for 2 days, then 8 sachets daily for 2 days
	Child 5-12 years: treat until impaction resolves or for maximum 7 days. Four sachets on 1st day, then increased in steps of 2 sachets daily to maximum of 12 sachets daily
	Ongoing maintenance (chronic constipation, prevention of faecal impaction)
	Child under 1 year: half to 1 sachet daily (non-BNFC recommended dose)
	Child 1-6 years: 1 sachet daily; adjust dose to produce regular soft stools (maximum 4 sachets daily)
	Child 6-12 years: 2 sachets daily; adjust dose to produce regular soft stools (maximum 4 sachets daily)
Osmotic laxatives
Lactulose	By mouth
	Child 1 month to 1 year: 2.5 ml twice daily, adjusted according to response
	Children 1-5 years: 2.5-10 ml twice daily, adjusted according to response (non-BNFC recommended dose)
	Children 5-18 years: 5-20 ml twice daily, adjusted according to response (non-BNFC recommended dose)
Stimulant laxatives
Sodium picosulphate b	Non-BNFC recommended doses
	By mouth
	Child 1 month to 4 years: 2.5-10 mg once a day
	Child 5-18 years: 2.5-20 mg once a day
Bisacodyl	Non-BNFC recommended doses
	By mouth
	Child 4-18 years: 5-20 mg once daily
	By rectum (suppository)
	Child 2-18 years: 5-10 mg once daily
Senna c	Sen nokot syrup
	By mouth
	Child 1 month to 4 years: 2.5-10 ml once daily
	Child 5-18 years: 2.5-20 ml once daily
	Senna (non-proprietary)
	By mouth
	Child 6-18 years: 1-4 tablets once daily
Docusate sodium d	By mouth
	Child 6 months-2 years: 12.5 mg three times daily (use paediatric oral solution)
	Child 2-12 years: 12.5-25 mg three times daily (use paediatric oral solution)
	Child 12-18 years: up to 500 mg daily in divided doses

^a Movicol Paediatric Plain not licensed for use in faecal impaction in children under 5 years, or for chronic constipation in children under 2 years
^b Elixir, licensed for use in children (age range not specified by manufacturer). Perles not licensed for use in children under 4 years
^c Syrup not licensed for use in children under 2 years
^d Adult oral solution and capsules not licensed for use in children under 12 years