This information is intended for use by health professionals

1. Name of the medicinal product

Manevac 12 Years Plus

2. Qualitative and quantitative composition

Each 5 g dose contains:

2.6 g Ispaghula seed (Plantago ovata Forssk.);

0.11g Ispaghula husk (Plantago ovata Forssk);

0.34 - 0.66g Tinnevelly Senna fruit (Cassia angustifolia Vahl), corresponding to 15 mg hydroxyanthracene glycosides calculated as sennoside B.

Excipients:

Each 5g dose contains 1.04g of sucrose (See Section 4.4. 'Special warnings and precautions for use')

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Brown, sugar-coated granules.

4. Clinical particulars
4.1 Therapeutic indications

For short-term relief of occasional constipation.

4.2 Posology and method of administration

For oral administration.

Method of administration:

Manevac 12 Year Plus should be placed dry on the tongue and, without chewing or crushing, swallowed with a glass of water, warm drink, milk, fruit juice or similar aqueous liquid; then maintain adequate fluid intake.

Posology:

Adults, the elderly and children over 12 years:

Using the measuring spoon provided, one or two level measuring spoons OR one or two sachets (equivalent to 5g or 10g of granules respectively) to be taken once daily at night at least ½ to 1 hour before or after intake of other medicines. Warning: not to be taken immediately prior to bed-time.

The maximum daily dose of hydroxyanthracene glycosides is 30 mg. This is equivalent to two level measuring spoons or two sachets (10g of granules) of Manevac 12 Year Plus. The correct individual dose is the smallest required to produce a comfortable soft-formed motion.

Normally it is sufficient to take this medicinal product up to two to three times a week.

Children under 12 years:

Should not be used in children or adolescents under the age of 12 years (see section 4.3).

Pregnant women:

One or two level measuring spoons OR one or two sachets (equivalent to 5g or 10g of granules respectively) once daily at night.

Duration of use:

Not to be used for more than 1 week. Usually it is sufficient to take this medicinal product up to two to three times during that week.

If the symptoms persist during the use of Manevac 12 Year Plus, a doctor or a pharmacist should be consulted.

See also section 4.4 Special warnings and precautions for use.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Cases of intestinal obstructions and stenosis, diseases of the oesophagus and cardia, paralysis of the intestine, or megacolon, appendicitis, inflammatory colon diseases (e.g. Crohn's disease, ulcerative colitis), abdominal pain of unknown origin, severe dehydration state with water and electrolyte depletion. Manevac 12 Year Plus should not be used by patients with diabetes mellitus, which is difficult to regulate.

Manevac 12 Year Plus should not be taken by patients who have difficulty in swallowing or any throat problems.

Children under 12 years of age.

4.4 Special warnings and precautions for use

Do not exceed the stated dose.

If abdominal pain occurs or in cases of any irregularity of faeces, the use of Manevac 12 Year Plus should be discontinued and medical advice must be sought.

If there is no bowel movement after three days, a doctor or pharmacist should be consulted.

Long-term use of stimulant laxatives should be avoided, as use for more than a brief period of treatment may lead to impaired function of the intestine and dependence on laxatives. If laxatives are needed every day the cause of the constipation should be investigated. This product should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration of bulk forming agents.

Prolonged excessive use may lead to fluid and electrolyte imbalance and hypokalaemia.

Intestinal loss of fluids may promote dehydration. Symptoms may include thirst and oliguria. In patients suffering from fluid loss where dehydration may be harmful (e.g. renal insufficiency, elderly patients) Manevac 12 Year Plus should be discontinued and only be restarted under medical supervision.

Stimulant laxatives (including Manevac 12 Year Plus) do not help with weight loss.

Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing QT-prolongation, diuretics, adrenocorticosteroids or liquorice root, have to consult a doctor before taking senna leaf preparation concomitantly.

Like all laxatives, Manevac 12 Year Plus should not be taken by patients suffering from faecal impaction and undiagnosed, acute or persistent gastro-intestinal complaints, e.g. abdominal pain, nausea and vomiting, unless advised by a doctor, because these symptoms can be signs of potential or existing intestinal blockage (ileus).

When products containing senna leaflet preparations are administered to incontinent adults, pads should be changed more frequently to prevent extended skin contact with faeces.

If the symptoms worsen during the use of Manevac 12 Year Plus, a doctor or a pharmacist should be consulted.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

In the package leaflet, the patient is informed about the following warning:

Does this help with weight loss?

Stimulant laxatives (including Manevac 12 Year Plus) do not help with weight loss. They do not reduce the absorption of calories or nutrients. They can cause watery stools (diarrhoea), abdominal cramps and dehydration. Dehydration can seem like weight loss.

Overuse of laxatives may damage your health by:

- Causing disturbances of electrolyte and mineral balances. Sodium, potassium, magnesium, and phosphorus are electrolytes and minerals that are present in very specific amounts necessary for proper functioning of the nerves and muscles, including those of the colon and heart. Upsetting this delicate balance can cause incorrect functioning of these vital organs.

Warning and precautions

Take each single dose of Manevac 12 Year Plus with 1-2 glasses of water or similar drink, such as milk or fruit juice. Taking Manevac 12 Year Plus without enough fluid may cause it to swell and block your throat, and may cause choking. If you have chest pain, vomiting, or difficulty in swallowing or breathing after taking Manevac 12 Year Plus, get medical attention straight away. (See “How to take Manevac 12 Year Plus” in section 3.).

Information for diabetics: Speak to your doctor before taking Manevac 12 Year Plus if you are diabetic (each measuring spoon or sachet contains approximately 1.04g of sucrose). If this applies to you it is important that you speak to your doctor pharmacist before taking Manevac 12 Year Plus and they will decide what to do. It may still be safe for you to take Manevac 12 Year Plus.

See your doctor before taking Manevac 12 Year Plus if you are already taking:

- Medicines for heart failure or irregular heart beats

- Any medicines that may affect your heart rhythm (QT-prolongation seen on an ECG trace)

- Water tablets(diuretics)

- Certain steroids used for inflammation

- Liquorice root.

- See also “Taking other medicines” below.)

- If you are incontinent, your pads should be changed more frequently.

- You should first try taking more exercise, changing your diet or taking bulking agents to relieve your constipation before taking laxatives. Ask your pharmacist or doctor for advise.

Other medicines and Manevac 12 Year Plus

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without prescription.

In particular tell your doctor or pharmacist about:

- Medicines for heart failure (cardiac glycosides)

3. How to take Manevac 12 Year Plus

It may be harmful to

• Take too much Manevac 12 Year Plus or

• Take Manevac 12 Year Plus for too long

This is because taking too much for too long may lead to:

- A 'lazy bowel', where the muscle in the bowel becomes too relaxed. This means that bowel emptying happens less often. This can lead to long-term constipation.

- Imbalance of fluid and salts in the body. This can affect the tightness of muscles such as those in the bowel. It can also affect the salts in the blood.

- Low levels of potassium in the blood (called 'hypokalaemia'). This can make you tired, dizzy, make your muscles weak and cause an uneven heart-beat.

Dehydration, making you thirsty, feel faint and giving you headaches. It can also mean you cannot pass enough urine.

The Label will state:

Front of the pack:

Does not help with weight loss

Overuse can be dangerous.

Back of the pack:

Do not take more medicine that the label tells you to.

Laxatives do not affect the number of calories absorbed from food.

If there is no bowel movement after 3 days, or if symptoms persist, in particular if you have persistent abdominal pain or are passing blood, consult your doctor.

4.5 Interaction with other medicinal products and other forms of interaction

Enteral absorption of concomitantly administered medicines such as minerals, vitamins (B12), cardiac glycosides, coumarin derivatives, carbamazepine and lithium may be delayed. For this reason Manevac 12 Year Plus should not be taken ½ to 1 hour before or after intake of other medicinal products.

If Manevac 12 Year Plus is taken together with meals by insulin dependent diabetic patients it may be necessary to reduce the insulin dose.

Use of Manevac 12 Year Plus concomitantly with thyroid hormones requires medical supervision because the dose of the thyroid hormones may have to be adjusted.

Hypokalaemia (resulting from long-term laxative abuse) potentiates the action of cardiac glycosides and interacts with antiarrhythmic medicinal products, with medicinal products, which induce reversion to sinus rhythm (e.g. quinidine) and with medicinal products inducing QT-prolongation.

Concomitant use with other medicinal products inducing hypokalaemia (e.g. diuretics, adrenocorticosteroids and liquorice root) may enhance electrolyte imbalance.

4.6 Fertility, pregnancy and lactation

Fertility

Studies on fertility have not been performed.

Pregnancy

There are no reports of undesirable or damaging effects during pregnancy and on the foetus when used at the recommended dosage schedule.

As a consequence of experimental data concerning a genotoxic risk of several anthranoids, e.g. emodin and aloe-emodin, the use is to be avoided during the first trimester. Manevac 12 Year Plus should only be used intermittently and if other actions like behavioural modification, dietary changes and use of bulk forming agents failed.

Lactation

Use during breast-feeding is not recommended as there are insufficient data on the excretion of metabolites in breast milk.

Small amounts of active metabolites (rhein) are excreted in breast milk. A laxative effect in breast fed babies has not been reported.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Flatulence may occur with the use of Manevac 12 Year Plus, this generally disappears in the course of the treatment. Manevac 12 Year Plus may produce abdominal pain and spasm and passage of liquid stools, in particular in patients with irritable colon. However, these symptoms may also occur generally as a consequence of individual overdosage. In such cases dose reduction is necessary.

Abdominal distension and risk of intestinal or oesophageal obstruction and faecal impaction may occur, particularly if swallowed with insufficient fluid.

Hypersensitivity reactions (pruritus, urticaria, local or generalised exanthema) may occur.

Chronic use may lead to disorders in water equilibrium and electrolyte metabolism and may result in albuminuria and haematuria.

Furthermore, chronic use may cause pigmentation of the intestinal mucosa (pseudomelanosis coli), which usually recedes when the patient stops taking the preparation.

Yellow or red-brown (pH dependent) discolouration of urine by metabolites, which is not clinically significant, may occur during the treatment.

The frequency is not known.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.yellowcard.mhra.gov.uk).

4.9 Overdose

Overdose may cause abdominal discomfort, flatulence and possibly intestinal obstruction due to the content of ispaghula. Adequate fluid intake should be maintained and management should be symptomatic.

The major symptoms of overdose/abuse are griping pain and severe diarrhoea with consequent losses of fluid and electrolytes, which should be replaced. Diarrhoea may especially cause potassium depletion, which may lead to cardiac disorders and muscular asthenia, particularly where cardiac glycosides, diuretics, adrenocorticosteroids or liquorice root are being taken at the same time.

Treatment should be supportive with generous amounts of fluid. Electrolytes, especially potassium, should be monitored. This is especially important in the elderly.

Chronic ingested overdoses of anthranoid containing medicinal products may lead to toxic hepatitis.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Laxatives

ATC-code: A 06 AB

The active substance ispaghula seed/husk is capable of absorbing up to 10 times its own weight in water and acts by hydration in the bowel. Gut motility and transit rate can be modified by ispaghula through mechanical stimulation of the gut wall as a result of the increase in intestinal bulk by water and the decrease in viscosity of the luminal contents or by contact with rough fibre particles. When taken with a sufficient amount of liquid (at least 30 ml per 1 g Manevac 12 Year Plus) ispaghula produces an increased volume of intestinal contents due to its highly bulking properties and hence a stretch stimulus, which triggers defaecation; at the same time the swollen mass of mucilage forms a lubricating layer, which makes the transit of intestinal contents easier.

The other active substance, senna pods contain 1,8-dihydroxyanthracene derivatives which possess a laxative effect. The β-O-linked glycosides (sennosides) are not absorbed in the upper gut; they are converted by bacteria of the large intestine into the active metabolite (rhein anthrone).

There are two different mechanisms of action:

1. stimulation of the motility of the large intestine resulting in accelerated colonic transit.

2. influence on secretion processes by two concomitant mechanisms viz. inhibition of absorption of water and electrolytes (Na+, Cl-) into the colonic epithelial cells (antiabsorptive effect) and increase of the leakiness of the tight junctions and stimulation of secretion of water and electrolytes into the lumen of the colon (secretagogue effect) resulting in enhanced concentrations of fluid and electrolytes in the lumen of the colon.

Defaecation takes place after a delay of 8 - 12 hours due to the time taken for transport to the colon and metabolisation into the active compound.

5.2 Pharmacokinetic properties

The active substance ispaghula seed / husk hydrates and swells to form a mucilage because it is only partially solubilised. Polysaccharides, such as those which dietary fibres are made of, must be hydrolysed to monosaccharides before intestinal uptake can occur. The sugar residues of the xylan backbone and the side chains of psyllium are joined by ß-linkages, which cannot be broken by human digestive enzymes.

Less than 10 % of the mucilage gets hydrolysed in the stomach, with formation of free arabinose. Intestinal absorption of the free arabinose is approximately 85 % to 93 %.

To varying degrees, dietary fibre is fermented by bacteria in the colon, resulting in production of carbon dioxide, hydrogen, methane, water, and short-chain fatty acids, which are absorbed and brought into the hepatic circulation. In humans, psyllium reaches the large bowel in a highly polymerised form that is fermented to a limited extent, resulting in increased faecal concentration and excretion of short-chain fatty acids.

The β-O-linked glycosides (sennosides) of the active substance senna pods are neither absorbed in the upper gut nor split by human digestive enzymes. They are converted by the bacteria of the large intestine into the active metabolite (rhein anthrone). Aglyca are absorbed in the upper gut. Animal experiments with radio-labeled rhein anthrone administered directly into the caecum demonstrated absorption < 10%. In contact with oxygen, rhein anthrone is oxidised into rhein and sennidins, which can be found in the blood, mainly in the form of glucuronides and sulphates. After oral administration of sennosides, 3 - 6% of the metabolites are excreted in urine; some are excreted in bile. Most of the sennosides (ca. 90%) are excreted in faeces as polymers (polyquinones) together with 2 - 6% of unchanged sennosides, sennidins, rhein anthrone and rhein. In human pharmacokinetic studies with senna pods powder (20 mg sennosides), administered orally for 7 days, a maximum concentration of 100 ng rhein/ml was found in the blood. An accumulation of rhein was not observed. Active metabolites, e.g. rhein, pass in small amounts into breast milk. Animal experiments demonstrated that placental passage of rhein is low.

5.3 Preclinical safety data

There are only data for ispaghula husk and psyllium without defining the exact test preparation available.

Single dose toxicity

The LD50 in rats was greater than the highest dose tested corresponding to 3,360 mg/kg ispaghula husk administered by gavage of an aqueous suspension. The LD50 in mice was greater than the highest dose tested corresponding to 2,940 mg/kg ispaghula husk also administered by gavage of an aqueous suspension. These studies were conducted prior to the establishment of good laboratory practices.

Subchronic toxicity

Psyllium was fed to rats at levels high as 10 % of the diet for periods up to 13 weeks (three 28-day studies, one 13-week study). Psyllium consumption ranged from 3,876 to 11,809 mg/kg/day. Because the absorption of psyllium is very limited, histopathological evaluations were limited to the gastrointestinal tract, liver, kidneys and gross lesions without observing any treatment-related effect. Effects considered to be biologically significant and related to psyllium supplementation were lower serum total protein, albumin, globulin, total iron-binding capacity, calcium, potassium, and cholesterol; and higher aspartate transaminase (AST) and alanine transaminase (ALT) activities relative to control. Several of these effects are considered to be secondary effects to others. The reasons for the lower serum total protein, albumin and globulin are not clear, but the absence of any increases in urinary protein, any evidence of gastrointestinal pathology, which could account for protein loss, and any differences in growth or feed efficiency in psyllium fed rats may give evidence that there are no adverse effect of psyllium on protein metabolism.

Reproductive toxicity

A rat multigeneration reproduction/teratology study showed no evidence of any adverse effects of psyllium on reproduction or development. Psyllium as 0, 1.25, or 5% (w/w) of the diet was administered in a standard (NIH-07) rat and mouse meal diet ad libitum through gestation of the third generation.

A segment II study in rabbits also showed no evidence of any adverse effect. Psyllium as 0, 2.5, 5 or 10% (w/w) of diet was administered in a purine certified rabbit chow diet for days 2 - 20 of gestation.

Genotoxicity and carcinogenicity

Tests on genotoxicity and carcinogenicity have not been performed.

Most data refer to senna pod extracts containing 1.4 to 3.5% of anthranoids, corresponding to 0.9 to 2.3% of potential rhein, 0.05 to 0.15% of potential aloe-emodin and 0.001 to 0.006% of potential emodin or isolated active constituents, e.g. rhein or sennosides A and B. The acute toxicity of senna pods, specified extracts thereof, as well as of sennosides in rats and mice was low after oral treatment. As a result of investigations with parenteral application in mice, extracts are supposed to possess a higher toxicity than purified glycosides, possibly due to the content of aglyca. In a 90-day rat study, senna pods were administered at dose levels from 100 mg/kg of up to 1,500 mg/kg. The tested drug contained 1.83 % sennosides A-D, 1.6 % potential rhein, 0.11 % potential aloe-emodin and 0.014 % potential emodin. In all groups epithelial hyperplasia of the large intestine of minor degree was found and was reversible within the 8-week recovery period. The hyperplastic lesions of the forestomach epithelium were reversible as well. Dose-dependent tubular basophilia and epithelial hypertrophy of the kidneys were seen at a dose of, or greater than 300 mg/kg per day without functional affection. These changes were also reversible. Storage of a brown tubular pigment led to a dark discoloration of the renal surface and still remained to a lesser degree after the recovery period. No alterations were seen in the colonic nervous plexus. A no-observable-effect-level (NOEL) could not be obtained in this study.

A 104-week study on rats of both genders did not reveal any carcinogenic effects with the same senna pods preparation at oral dosages of up to 300 mg/kg.

In addition a specified senna extract given orally for 2 years was not carcinogenic in male or female rats. The extract investigated contained approximately 40.8% of anthranoids from which 35% were sennosides, corresponding to about 25.2% of potential rhein, 2.3% of potential aloe-emodin and 0.007% of potential emodin and 142 ppm free aloe-emodin and 9 ppm free emodin.

Further 2-year studies on male and female rats and mice with emodin gave no evidence of carcinogenic activity for male rats and female mice, and equivocal evidence for female rats and male mice.

Sennosides displayed no specific toxicity when tested at doses up to 500 mg/kg in dogs for 4 weeks and up to 100 mg/kg in rats for 6 months.

There was no evidence of any embryolethal, teratogenic or foetotoxic actions in rats or rabbits after oral treatment with sennosides. Furthermore, there was no effect on the postnatal development of young rats, on rearing behaviour of dams or on male and female fertility in rats. Data for herbal preparations are not available.

An extract and aloe-emodin were mutagenic in in vitro tests, sennoside A, B and rhein gave negative results. Comprehensive in vivo examinations of a defined extract of senna pods were negative.

Chronic laxative use as a risk factor in colorectal cancer (CRC) was investigated in some clinical trials. Some studies revealed a risk for CRC associated with the use of anthraquinone-containing laxatives, some studies did not. However, a risk was also revealed for constipation itself and underlying dietary habits. The short-term use of senna pods as recommended can be regarded as safe.

6. Pharmaceutical particulars
6.1 List of excipients

Caraway oil

Spanish Sage oil

Peppermint oil

Acacia

Talc

Iron oxides E 172

Hard paraffin

Liquid paraffin

Sucrose

6.2 Incompatibilities

None known.

6.3 Shelf life

60 months (sachets)

36 months (250g composite container)

6.4 Special precautions for storage

Do not store above 30°C. (sachets)

Do not store above 25°C. (250g composite container)

6.5 Nature and contents of container

Sachet:

The sachet consists of 3 layers made of (from outside to inside): Paper, aluminium foil, polyethylene (PE).

Pack size: 6, 14 or 20 sachets with 5g of granules each.

Composite container with screw cap:

The composite container, cylindrical in shape with an inner lid and a screw cap both made of polypropylene (PP). The container consists of paper, aluminium foil and inner lacquer of PET with a base consisting of a tin plate.

Pack size: 250g

A 7ml measuring spoon (5g of granules) of polypropylene (PP) is added to all multi-dose containers.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

None stated.

7. Marketing authorisation holder

Mylan Products Ltd.,

Station Close,

Potters Bar,

Herts,

EN6 1TL,

United Kingdom.

8. Marketing authorisation number(s)

PL 46302/0132

9. Date of first authorisation/renewal of the authorisation

26/03/2009

10. Date of revision of the text

06/10/2020