Zeninas 30 coated tablets

The active principles are:

• Concentrated and dried juice of Aloe ferox (Cape Aloe): 60 mg (Equivalent to 15 mg of hydroxyanthracenic heterosides).
• Dried bark of Rhamnus purshianus DC (Cáscara Sagrada): 150 mg (Equivalent to 15 mg of hydroxyanthracenic heterosides).
• Dry extract of the dried bark of Rhamnus purshianus DC (Cáscara Sagrada) titrated to 20% in hydroxyanthracenic heterosides: 75 mg (Equivalent to 15 mg of hydroxyanthracenic heterosides).

Excipients: Cochineal red A (E124).

For the full list of excipients, see section 6.1.

pills

Symptomatic and temporary treatment of occasional constipation.

Orally.

- Adults and children over 12 years: 1 pill a day.

- Children: Do not use in children under 12 years of age.

Method of administration:

The pills are taken with a glass of water, 1 hour after dinner, preferably before going to bed; the laxative effect will be observed the next day in the morning.

Proper use of this medicine:

- Take at bedtime to get results in the morning.

- It is necessary to ingest at least 6 to 8 glasses of liquid daily to help generate soft stools and to protect the patient against dehydration when a large volume of water is lost with stool.

duration of use

Treatment should be short-term (do not take for more than 1 week). If symptoms persist after 4 days of treatment, a doctor or pharmacist should be consulted.

Hypersensitivity to the active substance or to any of the excipients.

This medicine should not be used when the following medical problems exist: appendicitis or abdominal pain of unknown origin, undiagnosed rectal bleeding, congestive heart failure, intestinal obstruction, hemorrhoids, severe liver disease, inflammatory diseases such as inflammatory disease of the colon (Crohn's disease and colitis ulcerative) and severe states of dehydration with reduced water and electrolytes. Do not administer to children (See section 4.4).

Prolonged use of laxatives should be avoided. If constipation or bowel irregularities persist for a long time (more than a week), the clinical situation should be examined.

Before using laxatives for the treatment of constipation, a treatment with foods rich in fiber, or fiber in concentrated form, should be tried.

Patients treated with cardiac glycosides, antiarrhythmics, drugs that prolong the QT curve, adrenocorticoid diuretics, or licorice root should consult a doctor before taking the drug.

As with all laxatives, it should be used with caution in patients suffering from fecal impaction or undiagnosed acute or persistent gastrointestinal complaints, for example abdominal pain, nausea or vomiting, as these symptoms may be signs of a potential or existing blockage. bowel (ileum).

Patients with renal disorders should be monitored to avoid possible electrolyte disturbances.

If this medication is administered to patients with incontinence, they should perform frequent diaper changes to avoid prolonged contact with feces.

Use in children

The use of laxatives in children under 12 years of age is not recommended. Before using laxatives in children, constipation must be diagnosed medically, and the existence of another disease (eg appendicitis) must be ruled out, and laxatives must only be used under medical criteria.

Use in the elderly

Its administration is not recommended.

prolonged use

Stimulant laxatives should not be used for more than 1 week, except for other medical criteria. If stimulant laxatives are taken for longer than the recommended period of time, impaired bowel function and laxative dependence may occur. Medications with Aloe and Cascara Sagrada should only be used if the therapeutic effect cannot be achieved with changes in eating habits or with bolus-forming agents.

In case of long-term abuse, disturbances of water and electrolyte metabolism caused by diarrhea may occur, especially potassium losses that can lead to disturbances of cardiac function and muscle weakness, especially if cardiac glycosides, diuretics and corticosteroids are taken simultaneously.

Chronic use can produce albuminuria and hematuria.

Urine coloration

Acute overdose or chronic misuse of this preparation may result in pink-yellow to brownish discoloration of the urine without pathological significance.

Coloration of the colonic mucosa

Chronic use of this medication may stain the colonic mucosa (Melanosis Coli) brown. Pigmentation in the colon appears from 7 to 14 weeks of treatment and disappears after one year of discontinuing it. Melanosis coli has no pathological significance.

Nephrotoxicity

Laxative abuse can cause hypokalemia due to the electrolyte imbalance caused by diarrhea. As long as renal function is not reduced this can lead to metabolic alkalosis. Potassium depletion reduces the functionality of the renal tubules and decreases the clearance of inulin, creatinine, and PAH.

Serum changes

Prolonged treatments can increase blood glucose concentration and also decrease serum potassium levels. If hypokalemia is severe (<2 mMol/L) it can lead to metabolic alkalosis and respiratory acidosis.

hypokalemia

In patients with primary hyperaldosteronism, Cushing's syndrome, Bartter's syndrome and other diseases that present with hypokalemia, potassium loss should be monitored due to the use of this medication, since it could exacerbate neuromuscular symptoms (muscle weakness in milder cases and rhabdomyolysis and myoglobinuria in the most severe) and cardiac (atrial and ventricular extrasystoles and in severe cases tachycardia and ventricular fibrillation).

excipients

- This medicine can cause allergic reactions because it contains cochineal red A (E124) as an excipient. May cause asthma, especially in patients allergic to acetylsalicylic acid. 

Interactions can cause the loss of therapeutic efficacy of any of the interacting products or a potentiation of their toxicity.

Cardiac glycosides : A potassium deficiency, consequence of chronic abuse, can cause an intensification of the action of cardiac glycosides.

Oral antibiotics : They can reduce the laxative effect by modifying the intestinal bacterial flora responsible for the hydrolysis of the prodrugs (glycosides) that give rise to the active ingredients.

Histamine H 2 receptor antagonists (Cimetidine, Famotidine and Ranitidine) : Simultaneous administration of this preparation with Histamine H 2 receptor antagonists may reduce the therapeutic effects of both.

Potassium-sparing diuretics : Serum potassium concentration may be reduced by promoting excessive potassium loss from the intestinal tract.

Indomethacin, acetylsalicylic acid and other prostaglandin synthesis inhibitors : Simultaneous administration of this preparation together with PGE2 synthesis inhibitors may reduce the therapeutic effect of both.

Chloramphenicol : A weakened laxative action has been described when taking chloramphenicol simultaneously.

Other drugs : Interacts with antiarrhythmic drugs, such as quinidine and with others that induce hypokalemia (eg corticosteroids, diuretics ) .

Interactions with diagnostic tests

With the results of diagnostic tests :

Urine Fenosulftalein (PSP) Test: Aloe and Cascara sagrada can color urine from pink to red, from red to violet, and from violet to brown.

With the physiological/analytical values :

Blood glucose concentrations: may increase after prolonged use. Serum Potassium Concentrations: May decrease due to increased excretion of potassium in the feces, especially with prolonged use or inadequate dosage.

Due to insufficient toxicological research, this medication should not be prescribed during pregnancy.

Animal studies have shown reproductive toxicity (see 5.3).

The risk in humans is unknown.

Small amounts of active metabolites (rhein) are excreted in breast milk and although there are no data on the possible laxative effects that these may have on infants, their use in this population is not recommended.

They have not been described.

Adverse reactions are listed in order of decreasing seriousness within each frequency range.

The adverse effects of the drug are mild and transient and are related to the dose.

At the indicated therapeutic doses (1 pill/day), there are no side effects,

At therapeutic doses in hypersensitive patients

At normal therapeutic doses, gastric and intestinal disorders, abdominal pain, colic, belching and cramps may appear.

At high doses or prolonged use

With prolonged use or in case of overdose, diarrhea may appear with consequent loss of water and electrolytes, particularly potassium. If the electrolyte imbalance is severe, it can cause confusion, cardiac arrhythmia, cramps, tiredness or weakness that may be more accentuated in the elderly. In the most serious cases, nephritis can occur due to the decrease in potassium.

chronic use

Melanosis Coli: Chronic use of anthraquinone-derived laxatives can color the colonic mucosa brown (Melanosis Coli) and color urine yellow to brown (or pink to purple) depending on pH. Pigmentation in the colon appears from 7 to 14 weeks of treatment and disappears after one year of discontinuing it. Melanosis coli has no pathological significance.

Cathartic colon: The cathartic colon has been defined on the basis of radiological findings in patients with chronic intake of laxatives. The changes found at the morphological level are: loss of haustration, dilated lumen, dilated terminal ileum, opening of the ileocecal valve and pseudonarrowing. The pathological changes found are: atrophy of the mucosa, superficial ulcerations, infiltrates in the submucosa (eosinophils and mononuclear cells), fibrosis of the muscularis mucosae and submucosa, and increased submucosal fat. These phenomena were observed in the 1950s but not in recent decades.

Habituation: A clear sign of chronic and inappropriate use of laxatives is the gradual loss of therapeutic effect.

The main symptoms are colic and severe diarrhea, with the consequent loss of fluid and electrolytes, which must be replaced. If the electrolyte imbalance is severe, it can cause confusion, cardiac arrhythmia, cramps, tiredness or weakness that may be more accentuated in the elderly. In the most serious cases, nephritis can occur due to the decrease in potassium.

The treatment consists of ingesting 15 grams of a mixture of 2 parts of activated carbon, 1 part of magnesium oxide and 1 part of tannic acid in half a glass of hot water. Fluid replacement, electrolytes especially potassium, and monitoring.

Pharmacotherapeutic group: Contact laxatives, ATC code: A06AB57.

Peristalsis or contact stimulant laxative.

The laxative effects are due to the associations of anthrones (mainly queen and aloe-emodin) generated by the hydrolysis of their corresponding O- and C-glycosides (prodrugs) by the bacterial flora of the large intestine. Anthrones seem to activate the generation of prostaglandin E2 and also stimulate chloride secretion and increase the concentration of water, potassium and other electrolytes in the colonic lumen.

Action mode

Laxative effect: It is produced through an action on the motility of the colon, which increases contractions, increasing peristalsis and decreasing transit time through the intestine. It seems that the influence on the motility of the small intestine (inhibition of the Na+/K+ pump and the Cl- channels in the colonic membrane) causes the acceleration of transit in the colon and that it also acts on the secretion processes (stimulation of secretion of mucus and chlorides) causes an increase in fluid secretion.

Defecation occurs 6-12 hours after treatment, the time necessary for the active ingredient to reach the colon.

Oral route: After the administration of Píldoras Zeninas, and due firstly to the pharmacokinetics of the O- and C-glucosides of anthraquinone that have minimal absorption in the stomach and intestine and secondly to the special formulation of the pill that practically does not disintegrate. in the stomach and small intestine, so the prodrugs reach the large intestine, after about 6 h, where the disintegration of the pill and the release of glycosides begin. The glycosides are hydrolyzed to their corresponding anthrones by the action of the microbial flora and the therapeutic effects begin to manifest. Anthrones and their corresponding anthraquinones are poorly absorbed in the large intestine, which is why most of the active principles are excreted directly with the faeces, either in free form and for the most part complexed with the faeces. A small proportion is absorbed and undergoes enterohepatic circulation where it is mainly metabolized to its sulfate and glucuronide derivatives as phase I metabolites.

sacred shell

There are no controlled pharmacokinetic studies regarding the plant or its extracts. It has been observed that the aglycones present in the drug are absorbed in the first gastrointestinal portion. However, beta-glucosides (prodrugs) are not absorbed or bound in that portion. These compounds are degraded in the colon by bacterial enzymes to anthrones, which are the active metabolites with a laxative effect.

Cape Aloe

There are no controlled pharmacokinetic studies regarding aloe preparations. The aglycones present in the drug are presumed to be absorbed in the first gastrointestinal portion. However, beta-glucosides (prodrugs) are not absorbed or bound in that portion. These compounds are broken down in the colon by bacterial enzymes to aloe-emodin anthrones, which are the active metabolites with a laxative effect.

Aloe

There are no new systematic preclinical trials for aloes or their formulations.

No teratogenic or foetotoxic effects have been observed in rats after oral administration with aloe extract (up to 1,000 mg/kg) or with aloin A (up to 200 mg/kg).

Some in vitro assays with aloemodin have shown genotoxicity. Positive results have been obtained in the Ames test with Salmonella typhimurium strains TA1537, TA1538, TA98 and TA1978. In the HPRT test, no reproducible induction of mutations was obtained, while unscheduled DNA synthesis and cell transformation were induced.

In "in vivo" studies (NMRI mouse bone marrow cell micronucleus assay; Wistar rat bone marrow cell chromosomal aberration assay; "mouse spot test" [DBA/2J x NMRI]) no indication of mutagenic activity of aloe-emodin

No specific toxicity in mice has been observed when extracts of aloe were administered orally at concentrations up to 50 mg/kg daily for 12 weeks and of aloin administered orally at doses up to 60 mg/kg daily for 20 weeks. .

Studies conducted in male and female rats and mice for 2 years with emodin showed no evidence of carcinogenic activity in male rats and female mice, and equivocal evidence for female rats and male mice.

sacred shell

There are no new studies on toxicity at single or repeated doses or related to reproductive toxicity.

Experimental studies carried out ¿in vitro¿ showed risk of genotoxicity of different anthranoids in the Salmonella microsome assay, the compounds aloe-emodin, emodin, chrysophanol and fiscion had a slight mutagenic action. No mutagenic effects were observed in the V79-HGPRT mutation test and in the unscheduled DNA synthesis (UDS) test for chrysophanol and fission. Emodin was mutagenic in the V79-HGPRT mutation test. In the UDS assay, emodin was an inducer of UDS in primary hepatocytes. Aloe-emodin showed a significant increase in the net kernel/nucleus ratio. Emodin was also tested for its in vitro transforming activity in C3H/M2 mouse fibroblasts. In the in vitro Salmonella/microsome mutagenesis and DNA repair assay in primary rat hepatocytes,

However, in ¿in vivo¿ studies of other plant compounds that contain anthranoids (senna) in rat hepatocytes (chromosomal aberration test, ¿spot test¿ in mice, UDS ¿in vivo/in vitro¿, did not show evidence of effects genetic.

In "in vivo" studies (NMRI mouse bone marrow cell micronucleus assay; Wistar rat bone marrow cell chromosomal aberration assay; "mouse spot test" [DBA/2J x NMRI]) no indication of mutagenic activity of aloe-emodin

Studies conducted in male and female rats and mice for 2 years with emodin showed no evidence of carcinogenic activity in male rats and female mice, and equivocal evidence for female rats and male mice.

Dietary exposure of high doses of anthroquinone peel glycosides to rats for 56 successive days did not cause apparent aberrant crypt foci (ACF) or an increased incidence of 1,2-dimethylhydrazine (DMH)-induced ACF. However, in rats treated with both DMH and high-dose glycosides, the mean number of aberrant crypts per focus, considered to be a consistent predictor of tumor development, was higher than in rats treated with DMH alone.

In rats treated with azoxymethane (AOM) and 140 and 420 mg/kg of cascara (alone or in combination) for 13 weeks, cascara did not induce the development of colonic aberrant crypt foci (ACF) and tumors and did not change the number of AOM-induced ACF and tumors at both doses.

The use of laxatives as a risk factor for colorectal cancer (CRC) has been investigated in different clinical studies. Some studies showed a risk of CRC associated with the use of anthraquinone-containing laxatives, while other studies did not. However, the risk was also seen for constipation itself and underlying eating habits. Further research is needed to definitively determine the carcinogenic risk.

Licorice, Gum Arabic, Magnesium Stearate, Talc, Quinoline Yellow E 104, Cochineal Red AE 124, Indigotine E 132, Polyethylene Glycol 6000.

Not applicable.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years.

Do not store at temperatures above 25°C.

Keep the blister tabs perfectly closed.

Three aluminum/pvc blister platelets, containing 10 pills each.

None special.

Disposal of unused medication and all materials that have been in contact with it will be done in accordance with local regulations.

Vemedia Manufacturing B.V.

Verrijn Stuartweg 60

NL-1112 AX Diemen

Netherlands

32735

Date of first authorization: 10/01/1959