Alfa Normix, 200 mg 12 pcs.

Pharmacological action Pharmacological action – antibacterial.

Pharmacodynamics

Rifaximin is a broad spectrum antibiotic of the rifamycin group. Like other representatives of this group it irreversibly binds beta-subunits of bacteria enzyme DNA-dependent RNA polymerase and, therefore, inhibits synthesis of RNA and proteins in bacteria.

As a result of irreversible binding to the enzyme, rifaximin exhibits bactericidal properties against sensitive bacteria. The drug has a wide spectrum of antimicrobial activity including most gram-negative and gram-positive, aerobic and anaerobic bacteria.

The wide antibacterial spectrum of rifaximin helps to reduce pathogenic intestinal bacterial load that causes some pathological conditions.

The drug reduces:

– production by bacteria of ammonia and other toxic compounds, which in the case of severe liver disease, accompanied by impaired detoxification process, play a role in the pathogenesis and clinical manifestations of hepatic encephalopathy;

– increased bacterial proliferation in gut microbial overgrowth syndrome;

– the presence of bacteria in the colonic diverticulum, which may cause inflammation in and around the diverticular sac and may play a key role in the development of symptoms and complications of diverticular disease;

– an antigenic stimulus that, in the presence of genetically determined defects in mucosal immunoregulation and/or protective function, may initiate or permanently maintain chronic intestinal inflammation;

The risk of developing infectious complications in colorectal surgery.

The mechanism of resistance. The development of resistance to rifaximin is due to reversible damage to the rpoB gene that encodes bacterial RNA polymerase. The incidence of resistant subpopulations among bacteria isolated from patients with traveler’s diarrhea was low.

According to clinical studies, a three-day course of rifaximin therapy in patients with traveler’s diarrhea was not accompanied by the occurrence of resistant Gram-positive (enterococci) and Gram-negative (E. coli) bacteria. When rifaximin was repeatedly administered at high doses in healthy volunteers and patients with inflammatory bowel disease, rifaximin-resistant strains appeared, but they did not colonize the GI tract or displace rifaximin-sensitive strains.

The resistant strains quickly disappeared when therapy was discontinued. Experimental and clinical data suggest that the use of rifaximin in patients with traveler’s diarrhea and latent Mycobacterium tuberculosis and Neisseria meningitidis infection will not be accompanied by selection of rifampicin-resistant strains.

Sensitivity. In vitro sensitivity testing cannot be used to determine the sensitivity or resistance of bacteria to rifaximin. There is currently insufficient clinical data to establish limits for evaluating sensitivity tests. Rifaximin was evaluated in vitro against traveler’s diarrhea pathogens from four regions of the world: enterotoxigenic and enteroaggregative strains of E. coli, Salmonella spp., Shigella spp., noncholera vibrios, Plesiomonas spp., Aeromonas spp. and Campylobacter spp. The MPC90 for the isolated strains was 32 μg/mL, and this level was easily attainable in the intestinal lumen as a result of the high concentration of rifaximin in the feces. Because rifaximin in polymorphic alpha has low gastrointestinal absorption and acts locally in the gut lumen, it may not be clinically effective against invasive bacteria even if these bacteria are sensitive to it in vitro.

Pharmacokinetics

Intake. Rifaximin in polymorphic form alpha is practically not absorbed when administered orally (less than 1%). When repeated administration in healthy volunteers and patients with damaged intestinal mucosa and inflammatory bowel disease, plasma concentrations are very low (less than 10 ng/ml). When using the drug 30 min after a fatty meal, an increase in systemic absorption of rifaximin of no clinical significance was observed.

Distribution. Rifaximin is moderately bound to plasma proteins. Protein binding in healthy volunteers is 67.5%, in patients with hepatic impairment – 62%.

Elimation. It is excreted unchanged in intestinal form (96.9% of the administered dose), because it is not degraded and metabolized during passage through the gastrointestinal tract.

Rifaximin detected with labeled isotopes in urine is not more than 0.025% of the oral dose. Less than 0.01% of the dose is excreted by the kidneys as 25-desacetylrifaximin, the only rifaximin metabolite identified in humans. Renal excretion of 14C rifaximin does not exceed 0.4%. Systemic exposure is nonlinear, dose-dependent, which is comparable to the absorption of rifaximin, possibly limited by the rate of dissolution.

Particular patient groups

With renal impairment. There are no clinical data on the use of rifaximin in renal failure.

With hepatic impairment. Systemic exposure in patients with hepatic impairment is greater than in healthy volunteers. Increased systemic exposure in these patients should be considered in light of the local action of rifaximin in the gut and its low systemic bioavailability, as well as available data on the safety of rifaximin in patients with cirrhosis.

Children. The pharmacokinetics of rifaximin in children have not been studied.

Indications

– acute gastrointestinal infections;

– traveler’s diarrhea;

– gut microbial overgrowth syndrome;

p> – hepatic encephalopathy;

– symptomatic uncomplicated diverticular disease of the colon;

– chronic inflammatory bowel disease.

Active ingredient

Composition

Each film-coated tablet contains:

The active ingredient:

Rifaximin with polymorphic structure alpha 200 mg.

Excipients:

sodium carboxymethyl starch 15 mg,

glyceryl palmitostearate 18 mg,

Colloidal silica 1 mg,

talc 1 mg,

microcrystalline cellulose 115 mg.

Film jacket:

hypromellose 5.15 mg,

titanium dioxide (E171) 1.5 mg,

Dinatrium edetate 0,02 mg,

Propylene glycol 0,5 mg,

Iron oxide (E172) 0,15 mg.

How to take, the dosage

Ingestion with a glass of water, regardless of meals.

The treatment of diarrhea. Adults and children over 12 years of age: 1 tablet of 200 mg, which is equivalent to 200 mg of rifaximin every 6 hours. Treatment of traveler’s diarrhea should not exceed 3 days.

Hepatic encephalopathy. Adults and children over 12 years of age: 2 tablets of 200 mg, equivalent to 400 mg of rifaximin every 8 hours.

Prevention of postoperative complications of colorectal surgery. Adults and children over 12 years: 2 tablets 200 mg, equivalent to 400 mg of rifaximin every 12 hours. Prophylaxis is given 3 days before surgery.

Bacterial overgrowth syndrome. Adults and children over 12 years: 2 tablets of 200 mg every 8-12 hours.

Symptomatic uncomplicated diverticulosis. Adults and children over 12 years of age: 1-2 tablets of 200 mg, equivalent to 200-400 mg of rifaximin every 8-12 hours.

Chronic inflammatory bowel disease. Adults and children over 12 years of age: 1-2 tablets of 200 mg, equivalent to 200-400 mg of rifaximin every 8-12 hours.

The duration of treatment with the drug Alfa Normix® should not exceed 7 days. The repeated course of treatment should be carried out not earlier than in 20-40 days. The total duration of treatment is determined by the clinical condition of patients. Doses and frequency of administration may be changed according to the doctor’s recommendation.

Dose adjustment is not required in elderly patients and patients with hepatic and renal insufficiency.

Interaction

In vitro studies show that Rifaximin does not inhibit cytochrome P450 isoenzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) and does not induce CYP1A2 and CYP2B6 but is a weak inducer of CYP3A4.

The clinical studies of drug interactions indicate that in healthy volunteers, rifaximin has no significant effect on the pharmacokinetics of drugs metabolized with participation of CYP3A4. In patients with impaired liver function it cannot be excluded that rifaximin may decrease exposure of CYP3A4 substrate drugs (e.g., warfarin, antiarrhythmic, anticonvulsant drugs) when used concomitantly with them, because in hepatic impairment it has higher systemic exposure compared to healthy volunteers.

In patients continuing warfarin and rifaximin, decreased and increased INR have been reported (in some cases with bleeding episodes). If co-administration is necessary, INR should be monitored closely at the beginning and end of treatment. Dose adjustments of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

In vitro studies suggest that rifaximin is a moderate P-gp substrate and is metabolized by the CYP3A4 isoenzyme.

It is not known whether drugs that inhibit CYP3A4 increase systemic exposure to rifaximin when used concomitantly with it. In healthy volunteers, co-administration of a single dose of cyclosporine (600 mg), a potent P-gp inhibitor, and a single dose of rifaximin (550 mg) resulted in 83- and 124-fold increases in the mean Cmax and AUC∞ of rifaximin. The clinical significance of this increase for systemic exposure is unknown. Potential interactions of rifaximin with other drugs that are eliminated from the cell by P-gp or other transport proteins (MRP2, MRP4, BCRP, BSEP) are unlikely.

Special Instructions

Clinical data indicate that the drug Alpha Normix® is ineffective in treatment of intestinal infections caused by Campylobacter jejuni, Salmonella spp., Shigella spp. which cause frequent diarrhea, fever, discharge of blood in stools. Alfa Normix® is not recommended for use in patients with fever and liquid stools with blood. Alpha Normix® should be discontinued if the symptoms of diarrhea worsen or persist for more than 48 hours. Other antibacterial therapy should be prescribed. Treatment of traveler’s diarrhea should not exceed 3 days.

It is known that Clostridium difficile-associated diarrhea can develop with almost all antibacterial agents, including Alpha Normix®. A potential association of Alpha Normix® with the development of Clostridium difficile-associated diarrhea and pseudomembranous colitis cannot be excluded. There is no experience with rifaximin combined with other rifamycins.

Caution should be exercised when concomitant administration of rifaximin and a P-gp inhibitor such as cyclosporine. Patients should be cautioned that although rifaximin is slightly absorbed (less than 1%), it may cause reddish staining of the urine: this is due to the active ingredient rifaximin, which, like most antibiotics of this series (rifamycins), has a reddish-orange coloring.

In case of superinfection caused by microorganisms insensitive to rifaximin, Alfa Normix® should be discontinued and appropriate therapy should be prescribed.

Due to the effect of Alpha Normix® on the intestinal flora, the effectiveness of oral contraceptives containing estrogens may decrease after its administration. It is recommended to use additional contraceptive measures when taking Alfa Normix® , especially if the estrogen content of oral contraceptives is less than 50 mcg.

The use of the drug Alpha Normix® is possible not earlier than 2 hours after taking activated charcoal.

Impact on the ability to drive vehicles, machinery. Although dizziness and somnolence are observed when using Alfa Normix®, but it does not influence significantly the ability to drive vehicles and to perform activities requiring high attention and quick psychomotor reactions. In case of dizziness and somnolence during the use of the drug it is necessary to refrain from performing the specified activities.

Contraindications

– Hypersensitivity to rifaximin or other rifamycins or any of the ingredients in the drug;

– Diarrhea with fever and liquid stools with blood;

– Intestinal obstruction (including partial obstruction).including partial);

– severe ulcerative bowel disease;

– children under 12 years of age (efficacy and safety not established).

With caution: renal failure, concomitant use with oral contraceptives, concomitant use with P-glycoprotein inhibitor such as cyclosporine.

Side effects

Side effects are classified by frequency as follows: very common (≥1/10), common (≥1/100 to ˂1/10), infrequent (≥1/1000 to ˂1/100), rare (≥1/10000 to ˂1/1000), very rare (˂1/10000), unknown (frequency cannot be determined based on available data).

Cardiovascular system disorders:

Infrequent: palpitations, “rushes” of blood to the skin of the face, increased blood pressure.

Blood disorders:

Infrequent: lymphocytosis, monocytosis, neutropenia.

Unknown: thrombocytopenia.

Immune system disorders:

Unknown: anaphylactic reactions, hypersensitivity, anaphylactic shock, laryngeal edema.

Metabolic disorders:

Infrequent: decreased appetite, dehydration.

Mental disorders:

Infrequent: abnormal dreams, depressed mood, insomnia, nervousness.

Anxiety of the central nervous system:

Often: dizziness, headache.

Infrequent: hypoesthesia, migraine, paresthesia, drowsiness, sinus headache.

Unknown: preconsciousness, agitation.

Visual side:

Infrequent: diplopia.

Internal ear:

Infrequent: ear pain, systemic dizziness.

Respiratory system disorders:

Infrequent: shortness of breath, dry throat, nasal congestion, oropharyngeal pain, cough, rhinorrhea.

Gastrointestinal and liver disorders:

Often: bloating, abdominal pain, constipation, diarrhea, flatulence, nausea, tenesmus, vomiting, urge to defecate.

Infrequent: pain in the upper abdomen, ascites, dyspepsia, abnormal gastrointestinal motility, mucus and blood discharge in stool, dry lips, “hard” stool, increased aspartataminotransferase activity, aguesia.

Unknown: impairment of hepatic functional tests, heartburn.

Urinary system disorders:

Infrequent: glucosuria, polyuria, pollakiuria, hematuria, proteinuria.

Skin and subcutaneous fatty tissue:

Infrequent: rash, sunburn.

Unknown: angioedema, allergic dermatitis, exfoliative dermatitis, eczema, erythema, pruritus, purpura, urticaria, erythematous rash, erythema of the palms, itching of the genitals.

Musculoskeletal system disorders:

Infrequent: back pain, muscle spasm, muscle weakness, myalgia, neck pain.

Infections:

Infrequent: candidiasis, herpes simplex, nasopharyngitis, pharyngitis, infections

upper respiratory tract.

Unknown: clostridial infection.

Reproductive system disorders:

Infrequent: polymenorrhea.

General symptoms:

Often: fever.

Infrequent: asthenia, pain and discomfort of uncertain location, chills, cold sweats, flu-like symptoms, peripheral edema, hyperhidrosis, facial edema, fatigue.

Laboratory tests: change in international normalized ratio.

Overdose

In patients with traveler’s diarrhea, doses of rifaximin up to 1800 mg/day were well tolerated, according to clinical studies. Even in patients with normal gut bacterial flora, rifaximin at doses up to 2400 mg/day for 7 days did not cause adverse symptoms.

In accidental overdose, symptomatic and supportive therapy is indicated.

Pregnancy use

The data on the use of Alpha Normix® in pregnancy are very limited.

Animal studies have shown a transient effect of rifaximin on fetal ossification and skeletal structure. The clinical significance of these results is unknown. The use of Alfa Normix® in pregnancy is not recommended.

It is not known whether rifaximin penetrates into breast milk. A risk to the breastfed baby cannot be excluded. To decide whether to continue rifaximin while breastfeeding, the balance of risk to the baby versus benefit to the mother must be evaluated.