Active ingredients: Bismuth subcitrate potassium, Metronidazole, Tetracycline hydrochloride
Pylera 140 mg / 125 mg / 125 mg capsules
Why is Pylera used? What is it for?
Pylera contains 3 different active ingredients: bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride.
Tetracycline and metronidazole belong to a group of medicines called antibiotics. The potassium subcitrate bismuth helps antibiotics treat the infection.
Pylera contains a group of medicines used to treat adult patients infected with Helicobacter pylori (H. pylori) who have or have had an "ulcer. H. pylori is a bacterium found in the lining of the stomach.
Pylera must be taken together with a medicine called omeprazole. Omeprazole is a medicine that works by reducing the amount of acid produced by the stomach. Concomitant administration of Pylera and omeprazole works by treating the infection and reducing the inflammation of the stomach lining.
Contraindications When Pylera should not be used
Do not take Pylera:
- if you are pregnant or breastfeeding
- if you are under the age of 12
- if you have kidney problems
- if you have liver problems
- if you are allergic (hypersensitive) to bismuth subcitrate potassium, metronidazole or other derivatives of nitroimidazole, tetracycline or any of the other ingredients of Pylera (see section 6).
Precautions for use What you need to know before taking Pylera
Talk to your doctor or pharmacist before taking Pylera.
Take special care with Pylera:
- if you need to have an X-ray examination as Pylera can alter the results
- if you need to have blood tests as Pylera can affect the results
- if your doctor has told you that you have an "intolerance to some sugars.
Avoid exposure to sunlight and sun beds while taking Pylera as the medicine may enhance their effects. Tell your doctor if you have sunburn.
Children and adolescents
Pylera capsules should not be given to children under the age of 12 and is not recommended for children between the ages of 12 and 18.
Interactions Which drugs or foods may change the effect of Pylera
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
In particular, tell your doctor if you take or have recently taken any of the following medicines:
- lithium, for the treatment of some mental illnesses
- medicines used to thin the blood or prevent blood clotting (eg warfarin)
- phenytoin and phenobarbital for epilepsy
- methoxyflurane (an anesthetic)
- other antibiotics, especially penicillin
- supplements containing iron, zinc, sodium bicarbonate
- co-administration of Pylera and other bismuth-containing drugs, if prolonged, may affect the nervous system
- busulfan and fluorouracil used for chemotherapy
- cyclosporine used to reduce the immune reaction after a transplant
- disulfiram used to treat alcoholism
- ranitidine used for indigestion and heartburn
- retinoids for skin disorders
- atovaquone to treat a "lung infection" Do not take antacids containing aluminum, calcium or magnesium with Pylera.
Pylera with food, drink and alcohol
Pylera should be taken with a full glass of water after main meals and at bedtime (preferably after a snack).
When taking Pylera and for the entire duration of treatment, you should avoid dairy products (such as milk or yogurt) or drinks with added calcium as they can alter the action of the medicine.
Alcohol should be avoided during therapy with Pylera and for at least 24 hours after its termination. Drinking alcohol while taking Pylera can cause unpleasant side effects such as nausea, vomiting, stomach pain (abdominal cramps), flushing and headache.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take Pylera if you are pregnant, could become pregnant during treatment or if you suspect that you are pregnant. Tell your doctor if you become pregnant while taking Pylera.
Do not breast-feed while taking Pylera as small traces of the components of Pylera pass into breast milk.
Driving and using machines
Do not drive or use any tools or machines if you feel dizzy, sleepy, have fits or have temporary blurred or double vision.
Pylera contains lactose and potassium
Pylera contains lactose, a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. Pylera contains approximately 96 mg of potassium per serving (3 capsules containing 32 mg of potassium each). To be taken into consideration in people with reduced kidney function or who follow a low potassium diet.
Dosage and method of use How to use Pylera: Dosage
Always take this medicine exactly as your doctor has told you. Pylera must be taken with a medicine called omeprazole. If in doubt, consult your doctor or pharmacist.
Adults and the elderly
Take 3 capsules of Pylera after breakfast, 3 capsules after lunch, 3 capsules after dinner and 3 capsules at bedtime (preferably after a snack), for a total of 12 capsules per day. Swallow the capsules whole with a full glass of water to avoid sore throat. It is important to complete the full course of treatment (10 days) and take all 120 capsules.
Take one omeprazole 20 mg capsule / tablet for breakfast and dinner with the doses of Pylera (for a total of 2 omeprazole capsules / tablets per day).
Pylera daily dosing schedule
If you forget to take Pylera
If you forget to take Pylera, take it as soon as you remember. However, if it is almost time for your next dose, do not take the missed dose. Do not take a double dose to make up for a forgotten dose.
If you miss more than 4 consecutive doses of Pylera (1 day), contact your doctor.
If you stop taking Pylera
It is important to complete the entire course of treatment, even if you will start to feel better after a few days.
If you stop Pylera too soon, the infection may not be fully cured and your symptoms may return or worsen. You may also develop resistance to tetracycline and / or metronidazole (antibiotics).
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Pylera
If you take more Pylera than the recommended daily dose, tell your doctor or go to the nearest emergency room. Take the bottle and any remaining capsules with you. So that your doctor is informed about the medicine you are taking.
Side Effects What are the side effects of Pylera
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Pylera and contact a doctor or go to a hospital immediately if you develop or notice any of the following:
- swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing
- itchy rash and lumps or hives
These can be signs of an allergic reaction.
- Severe skin adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)) (see "Frequency not known" below).
A serious but very rare side effect is a brain disease (encephalopathy). He has varying symptoms, but he may develop fever, neck stiffness, headache, and see or hear things that are not there. He may also have difficulty using his arms and legs, slurred speech, or feel confused. Tell your doctor immediately if you notice these side effects.
Other possible side effects
Very common (may affect more than 1 in 10 people):
- changes in the consistency or color of stools, including black colored stools
- diarrhea
- nausea
- bad taste or metallic taste
Common (may affect up to 1 in 10 people):
- abdominal pain
- constipation
- dry mouth
- He retched
- flatulence / bloating
- headache
- weakness
- feeling tired or lacking in energy
- feeling of general malaise
- vaginal infection with symptoms such as itching and irritation in the genital area, burning sensation or yellowish / white vaginal mucus
- increased concentrations of liver enzymes (transaminases) in blood tests
- black colored urine
- loss or decrease in appetite
- feeling of dizziness / feeling of mental confusion
- drowsiness
- skin problems such as redness (rash)
Uncommon (may affect up to 1 in 100 people):
- allergic reaction to the drug (with symptoms such as swelling of the face, lips, tongue or throat, which may cause difficulty in swallowing or breathing, or itchy rash and lumps or hives
- feeling of bloating / bloating
- belching
- open sore in the mouth / mouth ulcers
- changes in the color of the tongue (dark colored tongue)
- swelling of the tongue
- chest pain, chest discomfort
- yeast infections (candida), which can occur in the mouth (with symptoms such as white lesions) or in the genitals (severe itching, burning sensation, pain)
- numbness
- tingling / "pins and needles" sensation
- tremor
- anxiety, depression or sleep disturbances
- memory impairment
- skin problems such as itching or hives
- blurred (blurred) vision
- dizziness (spinning head)
Frequency not known (cannot be estimated from the available data):
- severe disease with blistering of the skin, mouth, eyes and genitals (Stevens-Johnson syndrome)
- severe disease with blistering of the skin (Lyell's syndrome, toxic epidermal necrolysis)
- flu-like symptoms, rash on the face subsequently extensive rash accompanied by elevated body temperature, elevated liver enzymes in blood tests, elevated levels of a type of white blood cell (eosinophilia), enlarged lymph nodes (DRESS)
- blistering and peeling of the skin (peeling of the skin)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and bottle after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage temperatures. Store in the original package to protect from light and moisture.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Pylera contains
The active ingredients are bismuth potassium subcitrate, metronidazole and tetracycline hydrochloride. Each capsule contains 140 mg of bismuth potassium subcitrate (equivalent to 40 mg of bismuth oxide), 125 mg of metronidazole and 125 mg of tetracycline hydrochloride.
The other ingredients are: magnesium stearate (E572), lactose monohydrate, talc (E553b), titanium dioxide (E171), gelatin and printing ink containing shellac, propylene glycol and red iron oxide (E172).
This medicine contains lactose and potassium. See paragraph 2.
What Pylera looks like and contents of the pack
Pylera capsules are white opaque, elongated hard capsules with the Aptalis Pharma logo printed on the body and 'BMT' printed in red ink on the cap. They contain a white powder and a smaller, white opaque capsule containing a yellow powder.
Pylera capsules are available in high-density polyethylene bottles containing 120 capsules.
A desiccant (silica gel) and a rayon swab are included in the bottle to protect the drug from moisture. Do not eat the desiccant or the rayon swab.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
PYLERA 140 MG / 125 MG / 125 MG CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each capsule contains 140 mg of bismuth potassium subcitrate (equivalent to 40 mg of bismuth oxide), 125 mg of metronidazole and 125 mg of tetracycline hydrochloride.
Excipients with known effect: each capsule contains 61 mg of lactose monohydrate and 32 mg of potassium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Capsule, hard (capsule)
Elongated, opaque white capsule with the Aptalis Pharma logo printed on the body and "BMT" printed in red ink on the cap. It contains a white powder and a smaller, opaque white capsule containing a yellow powder.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
In combination with omeprazole, Pylera is indicated for the eradication of infection with Helicobacter pylori and for the prevention of relapse of peptic ulcer in patients with ulcers from H. pylori active or past.
04.2 Posology and method of administration -
Dosage
Each dose of Pylera contains 3 identical hard capsules. Each dose should be taken 4 times a day: 3 capsules after breakfast, 3 capsules after lunch, 3 capsules after dinner and 3 capsules before bedtime (preferably after a snack), for a total of 12 capsules per day over a period of 10 One omeprazole 20 mg capsule / tablet (twice daily) should also be taken with the morning and evening dose of Pylera, for all 10 days of therapy.
Table 1 Daily dosing schedule for Pylera
In the case of one or more missed doses, the drug should be taken for more than 10 days, according to the normal dosage schedule, until the therapy is concluded. Patients should not take two doses at the same time. If more than 4 doses are missed. consecutive (1 day), the prescriber should be contacted.
Patients with renal or hepatic impairment
Pylera is contraindicated in patients with renal or hepatic impairment (see sections 4.3 and 4.4). The safety and efficacy of Pylera in patients with renal or hepatic impairment have not been evaluated.
Older people
Experience in elderly patients is limited. In general, the higher prevalence of impaired hepatic, renal or cardiac function and the presence of concomitant diseases with multiple therapies should be considered when prescribing Pylera to this patient population.
Pediatric population
Pylera is contraindicated in children below 12 years of age (see section 4.3) and is not recommended in children aged 12 to 18 years.
Method of administration
Oral use. Pylera and omeprazole should be taken after meals with a full glass of water (250 ml), this applies in particular to the dose taken at bedtime, to reduce the risk of developing oesophageal ulcer caused by tetracycline hydrochloride (see section 4.8. ).
04.3 Contraindications -
• Pregnancy and breastfeeding
• Pediatric population (up to the age of 12 years)
• Renal or hepatic impairment
• Hypersensitivity to the active substances, to other nitroimidazole derivatives or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use -
Rare cases of encephalopathy have been reported following prolonged treatment with excessive doses of various bismuth-containing products, which were reversible upon discontinuation of treatment. To date, no cases of encephalopathy due to the use of Pylera have been reported (see section 4.8).
Patients treated with metronidazole, usually for long periods of time, have experienced peripheral neuropathy. Although unlikely, the onset of abnormal neurological signs requires immediate discontinuation of Pylera. Use caution when administering Pylera to patients with central nervous system disease (see section 4.8).
During tetracycline therapy, patients may experience oral candidiasis, vulvovaginitis and anal pruritus, mainly due to proliferation of the Candida albicans, to be treated with an antifungal agent. In association, overgrowth of resistant coliform organisms such as Pseudomonas spp. And Proteus spp., which cause diarrhea.Sporadically, the use of tetracycline has resulted in more severe cases of enterocolitis due to superinfection with resistant staphylococci and pseudomembranous colitis due to Clostridium difficile. If superinfection occurs, Pylera should be discontinued and appropriate treatment initiated (see section 4.8).
Some individuals treated with tetracyclines have shown photosensitivity with an excessive sunburn reaction. Patients prone to exposure to direct sunlight or ultraviolet light should be warned that this reaction may occur when taking tetracycline-containing drugs. Treatment should be stopped at the first signs of skin rash.
Adequate fluid intake is recommended, especially for the dose of tetracycline hydrochloride taken at bedtime in order to reduce the risk of oesophageal irritation and ulcer (see section 4.8).
Metronidazole should be used with caution in patients with evidence or a history of blood dyscrasia. In rare cases, prolonged use of metronidazole has resulted in mild leukopenia (see section 4.8).
During treatment with Pylera it may be necessary to reduce the dose of oral anticoagulants such as warfarin (metronidazole may lengthen the prothrombin time). Prothrombin times should be monitored. There is no interaction with heparin (see section 4.5). The dose of warfarin may need to be reduced as omeprazole may slow its elimination.
The consumption of alcoholic beverages should be avoided during Pylera therapy and for at least 24 hours following its termination (see section 4.5).
In adults, the use of tetracycline has been associated with pseudotumor cerebri (benign intracranial hypertension), the typical clinical manifestations of which are headache and blurred vision. Although this disorder and related symptoms generally disappear soon after tetracycline discontinuation, permanent sequelae are possible ( see sections 4.8 and 4.5 for interactions with retinoids).
Myasthenic syndrome has rarely been observed in association with tetracycline. Caution is advised in patients with myasthenia gravis as the disease may worsen (see section 4.8).
Concomitant use of tetracycline and methoxiflurane has been reported to cause fatal renal toxicity. Therefore, the use of methoxiflurane in patients treated with Pylera should be avoided.
Pylera contains approximately 96 mg of potassium per serving (3 capsules containing 32 mg of potassium each). To be taken into consideration in people with reduced kidney function or who follow a low potassium diet.
Pylera also contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Bismuth absorbs X-rays and can interfere with diagnostic radiological procedures of the gastrointestinal tract.
With bismuth, the faeces can temporarily take on a black color with a harmless effect. However, this is an effect that does not interfere with standard occult blood tests.
Metronidazole can interfere with the values of some blood tests such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase. Values can be obtained All tests in which this interfering effect of metronidazole was observed involved a nicotinamide redox coupled enzyme assay (NAD). The interference is due to the similarity of the adsorption peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
04.5 Interactions with other medicinal products and other forms of interaction -
No interaction studies have been performed with Pylera. Therefore, the interactions observed with the different active ingredients of Pylera are listed below, as indicated in their respective Summary of Product Characteristics or described in the literature.
In patients treated with Pylera, the need for concomitant administration of other drugs should be checked prior to treatment. Although no specific interactions associated with concomitant therapy have emerged, patients treated concurrently with several other drugs are generally more at risk of developing side effects and therefore caution should be exercised in their treatment.
Interactions with bismuth
Ranitidine increases the absorption of bismuth.
Omeprazole increases the absorption of bismuth. To reduce the absorption of bismuth it is therefore recommended to take Pylera and omeprazole on a full stomach.
Interactions with metronidazole
Lithium
Some cases have shown that metronidazole may accelerate the onset of signs of lithium toxicity in patients treated with high doses of lithium. Close monitoring of lithium levels is recommended in these patients.
Alcohol / disulfiram
Metronidazole causes a well documented disulfiram-like reaction with alcohol (abdominal cramps, nausea, vomiting, headache, flushing). Psychotic reactions have been reported in alcoholic patients on metronidazole who have used disulfiram within the previous 2 weeks.
Anticoagulants
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of the prothrombin time. Therefore, the dose of anticoagulant drug should be monitored and adjusted during treatment with Pylera.
Phenytoin, phenobarbital
Co-administration of medicinal products that stimulate liver microsomal enzymes such as phenytoin or phenobarbital may accelerate the elimination of metronidazole, resulting in decreased plasma levels. In such cases, impairment of phenytoin clearance has also been observed. Relevance is unknown. of reduced systemic exposure to metronidazole since the relative role of systemic antimicrobial anti-microbial activity has not been establishedHelicobacter pylori than the local one.
5-Fluorouracil
Metronidazole reduces the clearance of 5-Fluorouracil and may therefore cause increased toxicity of 5-Fluorouracil.
Cyclosporine
Patients treated with cyclosporine are at risk of higher serum levels of cyclosporine. Serum concentrations of cyclosporine and creatinine should be closely monitored when co-administering the two drugs.
Busulfan
Metronidazole can increase busulfan plasma levels, which can lead to severe busulfan toxicity.
Interactions with tetracycline
Methoxyflurane
Concomitant use of tetracycline and methoxyflurane has been reported to cause fatal renal toxicity.
Anticoagulants
Tetracycline has been shown to reduce plasma prothrombin activity. Therefore, frequent monitoring of anticoagulant therapy with adequate adjustment of anticoagulant dosage should be ensured during treatment with Pylera.
Penicillin
Since bacteriostatic drugs, such as the tetracyclines class of antibiotics, can interfere with the bactericidal action of penicillin, it is not advisable to administer these drugs at the same time.
Antacids, iron and dairy preparations
Antacids containing aluminum, calcium or magnesium, preparations containing iron, zinc or sodium bicarbonate or dairy products interfere with the absorption of tetracycline. The clinical relevance of reduced systemic exposure to tetracycline is unknown as the relative role has not been established. of the "systemic antimicrobial activity anti-Helicobacter pylori than the local one. Therefore these products should not be used concomitantly with Pylera.
Retinoids
Co-administration of retinoids and tetracyclines has been observed to cause an increase in the incidence of benign intracranial hypertension and should therefore be avoided (see section 4.4).
Consideration should be given to discontinuing retinoid administration during the short period of treatment with Pylera.
Atovaquone
Tetracycline may reduce the plasma concentrations of atovaquone.
04.6 Pregnancy and breastfeeding -
Pregnancy
Based on human experience, tetracycline hydrochloride (a component of Pylera), when administered during pregnancy, has effects on dental and skeletal development.
Pylera is contraindicated during pregnancy (see section 4.3).
There are no data on the use of Pylera in pregnant women.
There are no animal data on the effects of potassium subcitrate bismuth. Animal studies, related to the effects of colloidal bismuth subcitrate (which is similar to potassium subcitrate bismuth in terms of physico-chemical, structural, biological (in vitro) and pharmacokinetics) and metronidazole on reproductive toxicity are insufficient.
Fertility
Animal studies with metronidazole and tetracycline hydrochloride (two components of Pylera) have shown impaired male fertility. There are no animal data on the effects of bismuth subcitrate potassium. Data, obtained from animal studies, on the effects of colloidal subcitrate bismuth (which is similar to potassium subcitrate bismuth in terms of physico-chemical, structural, biological (in vitro) and pharmacokinetics) on reproductive toxicity are insufficient (see section 5.3).
Feeding time
Metronidazole is excreted in breast milk in concentrations similar to those found in plasma.
It is unknown whether bismuth subcitrate potassium or its metabolites are excreted in human milk.
Tetracycline hydrochloride is excreted in breast milk and effects on the dental development of breastfed infants / children of women treated with tetracycline hydrochloride have been observed. Pylera is contraindicated during lactation (see section 4.3).
04.7 Effects on ability to drive and use machines -
Given the known pharmacodynamic properties of the active substances of Pylera, no effects on the ability to drive and use machines are expected. However, no clinical studies have been conducted to document their absence.
Convulsions and dizziness have been reported in patients treated with metronidazole. In adults, the use of tetracycline has been associated with pseudotumor cerebri (benign intracranial hypertension), the clinical manifestations of which include transient blurred vision (see section 4.8). Patients should be informed of the potential for these adverse reactions and advised not to drive or operate machinery if such symptoms occur.
04.8 Undesirable effects -
to. Summary of the safety profile
Adverse reactions with Pylera in combination with omeprazole observed in controlled clinical trials are consistent with the known safety profile of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride administered separately.
The most common (very common) adverse reactions observed during treatment with Pylera include, with decreasing frequency: abnormal stools, diarrhea, nausea and dysgeusia (including a metallic taste).
Serious skin adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome: life-threatening) have been observed with the use of Pylera and its individual components, metronidazole and tetracycline. In case of adverse skin reactions severe, Pylera treatment should be stopped immediately.
b. Tabulated list of adverse reactions
The adverse reactions listed below are from pooled data from three phase 3 controlled clinical trials (540 patients exposed to Pylera) and from post-marketing experience (including spontaneous reports, publications and regulatory authority reports).
Adverse reactions are listed by frequency according to the following categories: very common (≥1 / 10); common (≥1 / 100,
* Low Level Term (LLT); ** high-level term (HLT)
MedDRA, version 11.0
c. Description of a selection of adverse reactions
Black stools and tongue discoloration can occur with bismuth compounds, due to conversion to bismuth sulfide in the gastrointestinal tract; stomatitis has been attributed to bismuth salts, but has also been observed in association with the use of metronidazole.
Like other antimicrobial agents, tetracycline can cause superinfections. Candidiasis (oral and vaginal) is probably due to tetracycline.
Dizziness, dysgeusia, headache and chromaturia (dark colored urine) are most likely attributable to metronidazole.
Transient and reversible elevations in transaminases have been observed in clinical studies of Pylera.
Adverse reactions observed in association with bismuth compounds, not reported with Pylera.
• Encephalopathy has been associated with the use of high doses of different bismuth salts over an extended period of time.
Adverse reactions observed in association with metronidazole.
• Reversible leuko-neutropenia in cases of prolonged treatment. In rare cases, reversible thrombocytopenia.
• Seizures associated with metronidazole therapy (usually at high doses or in patients with renal impairment).
• Patients treated with metronidazole, usually over a long period of time, have experienced peripheral neuropathy. Withdrawal of metronidazole or dose reduction generally results in complete resolution or improvement of the neuropathy which, however, may persist in some patients despite these measures.
• Anaphylaxis, dysuria, cystitis, incontinence, pancreatitis and pseudomembranous enterocolitis.
• Very rare cases of encephalopathy, cholestatic hepatitis with jaundice have been reported with metronidazole.
Adverse reactions observed in association with tetracycline hydrochloride, not reported with Pylera.
• Pseudomembranous colitis caused by the proliferation of Clostridium difficile it is a potential complication of tetracycline use; as with other antibiotics, other superinfections can occur.
• Hepatic failure has been reported in patients treated with high doses of tetracycline and in patients with renal impairment.
• There have been reports of renal dysfunction due to tetracycline, particularly deterioration in patients with pre-existing renal impairment. These effects are dose related. In rare cases, acute renal failure and interstitial nephritis have occurred.
• Permanent discoloration of the teeth may occur during tooth development. Cases of enamel hypoplasia have also been reported.
• Cases of oesophageal ulcer have been reported with tetracycline, especially after ingestion of the capsules or tablets with insufficient water at bedtime.
• The use of tetracycline is also associated with haemolytic anemia, thrombocytopenic purpura, neutropenia and eosinophilia, although in rare cases.
• There have been reports of pseudotumor cerebri (benign intracranial hypertension) in adults and protrusion of the fontanelles in neonates in patients treated with tetracycline.
• Increased muscle weakness (myasthenic syndrome) has occasionally been reported following the use of tetracycline in patients with myasthenia gravis.
• A photosensitivity reaction, which has been reported with most tetracycline antibiotics, occurs in very rare cases following the use of tetracycline; and appears to be phototoxic rather than photoallergic in nature. Paresthesia may be a sign. of imminent phototoxicity.
• Pharyngitis, anaphylaxis, exfoliative dermatitis and pancreatitis.
d. Pediatric population
Pylera is contraindicated in patients under the age of 12 and should not be used in children between the ages of 12 and 18.
And. Other particular populations
Older people
Experience with Pylera in elderly people is limited. No specific safety risks have been identified.
Hepatic impairment
Temporary mild to moderate elevations in liver enzymes were observed in clinical studies of Pylera.Pylera is contraindicated in patients with hepatic impairment (see section 4.3).
Renal impairment
Pylera is contraindicated in patients with renal impairment (see section 4.3). Renal failure was not associated with Pylera in clinical studies.
f. Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
In the event of an overdose, patients should contact a physician, poison control center or emergency room.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: combinations for the eradication of Helicobacter pylori.
ATC code: A02BD08.
Pylera is a fixed triple combination capsule containing bismuth potassium subcitrate, metronidazole and tetracycline hydrochloride for the eradication of H. pylori in combination with omeprazole (quadruple therapy).
Mechanism of action
Bismuth
The precise action of bismuth in the treatment of infections from H. pylori it is still unknown. It appears to be related to direct toxicity on membrane function, inhibition of protein and cellular synthesis, inhibition of urease enzyme activity, prevention of cytoadherence, ATP synthesis, and non-specific competitive interference with iron transport.
Metronidazole
The antimicrobial mechanism of action of metronidazole depends on the reduction of its nitro group by nitroreductase and other reductases to nitroanionic radicals. These radicals damage the DNA of the bacteria, causing a process of cell death.
Tetracycline
Tetracycline binds specifically to the 30S ribosome and prevents tRNA from accessing the mRNA-ribosome complex, interfering with protein synthesis.
Relationship between pharmacokinetics and pharmacodynamics
Bismuth
The PK / PD relationship in subcitrate bismuth has not been established.
Metronidazole
Efficacy mainly depends on the Cmax (maximum serum concentration) / MIC (minimum inhibitory concentration) ratio of the pathogen and the AUC (area under the curve) / MIC ratio of the pathogen, respectively.
Tetracycline
Efficacy depends primarily on the pathogen's AUC (area under the curve) / MIC ratio.
Resistance mechanism (s)
Bismuth
Resistance to bismuth in Gram-negative bacteria has been shown to depend on iron and its absorption. The resistance to the inhibitory action of bismuth is inversely related to the iron concentration and largely depends on the iron transport mechanisms.
Metronidazole
In the"Helicobacter pylori resistance is related to mutations in the gene encoding NADPH nitroreductase. These mutations prevent the nitroreductase from reducing the nitro group of metronidazole.
Tetracycline
The three main resistance mechanisms that have been described are the following:
• a reduction in the accumulation of tetracycline due to a reduction in antibiotic inflow or the acquisition of an energy-dependent pathway,
• a reduction in the access of tetracycline to the ribosome due to the presence of protective proteins of the ribosome, and
• an "enzymatic inactivation of tetracyclines.
There is complete cross-resistance between metronidazole and other imidazoles and between tetracycline and other tetracyclines.
Breakpoint
Bismuth
The species-related breakpoints for bismuth and l "H. pylori they have not been determined by EUCAST (European Committee of Antimicrobial Susceptibility Tests).
Metronidazole
Testing for metronidazole is performed using typical dilution series. The minimum inhibitory concentrations for metronidazole susceptible and resistant microorganisms are given below.
EUCAST Breakpoint:
* mainly based on serum pharmacokinetics
Tetracycline
Species-related breakpoints for tetracycline e H. pylori have not been determined by EUCAST. However, for tetracycline and H. pylori a resistance breakpoint of 4 mg / L was used.
Prevalence of acquired resistance
The prevalence of resistance for the "Helicobacter pylori varies by geographic area and time. Local resistance data is therefore desirable, especially to ensure adequate treatment of severe infections. If the local resistance situation questions the efficacy of Pylera, an expert consultation should be sought. Especially in the case of severe infection or therapeutic failure, a microbiological diagnosis with confirmation of the microorganism and its sensitivity to the active ingredients of Pylera is required. .
Currently the resistance rate of Helicobacter pylori tetracycline is considered to be less than 5%, while the resistance rate to metronidazole is approximately 30-50%. Clinical data indicate a slight decline in the eradication rate of H. pylori after treatment with Pylera in patients with metronidazole-resistant strains.
Clinical efficacy and safety
Two comparative studies were conducted, one in Europe (pivotal study) and one in the United States (complementary study), comparing Pylera in combination with omeprazole for 10 days vs. the standard regimen omeprazole, amoxicillin and clarithromycin (OAC) for 7 and 10 days, respectively. Both studies had a non-inferiority, randomized, parallel-group, open-label, active-controlled design and included subjects with H. pylori confirmed. The results are summarized in the following table. In both studies and for both treatment groups, compliance was greater than 95%.
In order to evaluate the impact of antibiotic resistance, biopsies were performed for the determination of cultures and the resistance of bacterial strains to clarithromycin and metronidazole was tested. The minimum inhibitory concentration (MIC) that defines the sensitivity was ≤8 mcg / ml for metronidazole e
The main European study also investigated the impact of ulcers on treatment efficacy. The efficacy of Pylera was similar in patients with a history of active or previous peptic ulcer and in patients without a peptic ulcer.
Safety data from these studies are included in the pooled information provided in section 4.8.
Pediatric population
The European Medicines Agency has waived the obligation to conduct studies with Pylera in all subsets of the pediatric population as the medicine is likely to be unsafe (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties -
Bismuth subcitrate potassium (bismuth)
The elimination half-life of bismuth subcitrate potassium in plasma and blood is relatively long, therefore accumulation of this active substance is observed after 4 repeated doses of Pylera administered concomitantly with omeprazole 20 mg twice daily for 10 days. Steady-state bismuth in plasma and blood was generally detected by Day 4. On Day 10, mean concentrations were below 50 mcg / l in all subjects. However, in sporadic cases a percentage of subjects (12 and 8 out of 28 for plasma and blood concentrations) also showed concentrations higher than 50 mcg / l, with values higher than 100 mcg / l in 2 patients (in one case for both concentrations, in the other only for the concentration plasma), although these were transient increases lasting less than 1 hour at each episode.
At each draw up to Day 10 and steady state on Day 10 there were no marked differences between plasma and blood bismuth concentrations, demonstrating the distribution of bismuth in the blood cell compartment. The apparent terminal elimination half-life (T½el) of bismuth in plasma was estimated to be between 21 and 90 hours. Conversely, due to the possible association of bismuth with blood cells, the T½el of bismuth in blood was longer (between 192 and 605 hours, in individual subjects).
Metronidazole
After oral administration, metronidazole is well absorbed and peak plasma concentrations occur 1-2 hours after dosing. The plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 500 mg produces a peak plasma concentration of approximately 12 mcg / ml.
Metronidazole is present in plasma mainly as an unchanged compound, with lower amounts of the 2-hydroxymethyl metabolite. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole is also present in cerebrospinal fluid, saliva and breast milk in concentrations similar to those in plasma.
The mean elimination half-life of metronidazole in healthy volunteers is 8 hours. The primary route of elimination of metronidazole and its metabolites is urine (60-80% of the dose), faecal excretion is estimated at 6-15 % of the dose. Metabolites present in urine are mainly derived from side chain oxidation [1- (β-hydroxyethyl) 2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation. Unchanged metronidazole accounts for about 20% of the total. Renal clearance of metronidazole is approximately 10 ml / min / 1.73 m³.
Reduced renal function does not alter the single dose pharmacokinetics of metronidazole. The plasma clearance of metronidazole is reduced in patients with hepatic impairment.
Tetracycline hydrochloride
Tetracycline is absorbed (60-90%) in the stomach and upper small intestine. The presence of food, milk or cations can significantly reduce the extent of absorption. In plasma, tetracycline exhibits varying degrees of binding. with plasma proteins It is concentrated by the liver in the bile and excreted in the urine and faeces at high concentrations in the biologically active form.
Tetracycline is distributed in most tissues and body fluids. It is distributed in the bile and undergoes various degrees of enterohepatic recirculation. Tetracycline tends to localize in tumor tissue, necrotic or ischemic, in the liver and spleen, and to form complexes of tetracycline-calcium orthophosphate in the sites of new bone formation or dental development. Tetracycline easily crosses the placenta and is excreted in high percentage in breast milk.
Pylera capsules
The clinical relevance of systemic versus local concentrations of the active substances for the "antimicrobial activity of Pylera against" has not been established.Helicobacter pylori. A comparative bioavailability study was conducted on metronidazole (375 mg), tetracycline (375 mg) and bismuth subcitrate potassium (420 mg, equivalent to 120 mg bismuth oxide (Bi2O3)) administered as Pylera or in 3 separate capsule formulations. , at the same time as healthy male volunteers. The pharmacokinetic parameters of the individual active substances, administered as Pylera or in the three separate formulations, were similar.
The pharmacokinetic parameters of metronidazole, tetracycline hydrochloride and bismuth were also determined by fasting and fed Pylera administration. Food reduced the systemic absorption of all three active substances in Pylera, with a reduction in AUC of 6%, 34% and 60% for metronidazole, tetracycline hydrochloride and bismuth, respectively. This reduction in the absorption of all three active substances of Pylera in the fed state is not considered clinically significant. The increase in gastric retention time may have a beneficial effect as it may prolong the exposure of H. pylori to bismuth, metronidazole and tetracycline hydrochloride. Pylera should be taken after meals (breakfast, lunch and dinner) and before bedtime (preferably with a snack), in combination with omeprazole twice daily (breakfast and dinner) (see section 4.2).
Omeprazole capsules
The effect of omeprazole on bismuth absorption was evaluated in 34 healthy volunteers treated with Pylera (QID) with or without omeprazole (20 mg BID) for 6 days. In the presence of omeprazole the absorption of the bismuth contained in Pylera is significantly increased compared to the absence of omeprazole. The Cmax and AUC values for Pylera without omeprazole were 8.1 (84% CV) and 48.5 (28% CV), respectively. While for Pylera in combination with omeprazole the Cmax and AUC are respectively 25.5 (69% CV) and 140.9 (42% CV). Concentration-dependent neurotoxicity is associated with prolonged use of bismuth and it is possible that occur with short-term intake or at steady-state concentrations below 50 ng / mL. After multiple doses of Pylera in combination with omeprazole one subject had a temporary maximum bismuth concentration (Cmax) greater than 50 ng / mL ( 73 ng / mL). The patient had no symptoms of neurotoxicity during the study. There is no clinical evidence indicating that "short-term exposure to Cmax values above 50 ng / mL is associated with neurotoxicity.
The impact of renal and hepatic impairment on Pylera exposure has not been evaluated, although exposure to metronidazole and tetracycline hydrochloride has been studied (see sections 4.2, 4.3, 4.4 and 4.8).
05.3 Preclinical safety data -
No non-clinical studies have been performed to evaluate the effect of combined use of bismuth subcitrate potassium, tetracycline hydrochloride and metronidazole.
Non-clinical data, where available for colloidal subcitrate bismuth (which is similar to potassium subcitrate bismuth in terms of physicochemical, structural, biological (MIC in one study) in vitro) and pharmacokinetic characteristics), reveal no special risk for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
Non-clinical data, where available, for tetracycline hydrochloride reveal no special hazard for humans based on studies of repeated dose toxicity, genotoxicity and carcinogenic potential.
Fertility was impaired in male rats (effects on sperm and testes). The results of animal studies indicate that tetracycline crosses the placenta, is present in fetal tissues and can have toxic effects on the development of the fetus (often related to a developmental delay of the skeletal system). Evidence of embryotoxicity was observed in animals treated in early pregnancy. Tetracycline is excreted in the milk of female rats.
Non-clinical data, where available, for metronidazole reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity and genotoxicity. Metronidazole was found to be carcinogenic in mice and rats. Fertility was impaired in male mice and rats (effects on sperm and testes). Metronidazole is not teratogenic in mice, rats or rabbits.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Magnesium stearate (E572)
Talc (E553b)
Lactose monohydrate
Capsule shell:
Titanium dioxide (E171)
Jelly
Printing ink:
Red iron oxide (E172)
Shellac
Propylene glycol
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
This medicinal product does not require any special storage temperatures. Store in the original package to protect from light and moisture.
06.5 Nature of the immediate packaging and contents of the package -
HDPE bottle with child resistant closure, rayon wad and desiccant (silica gel).
Pack of 120 capsules.
06.6 Instructions for use and handling -
Medicines should not be disposed of via wastewater or household waste. Unused medicine and waste derived from this medicine should be disposed of in accordance with local regulations. This will help protect the environment.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Allergan Pharmaceuticals International Limited
Clonshaugh Industrial Estate
Coolock
Dublin 17
Ireland
08.0 MARKETING AUTHORIZATION NUMBER -
AIC 041527019
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
February 21, 2014
10.0 DATE OF REVISION OF THE TEXT -
09/2016
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -
