Unidox solutab®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT UNIDOX SOLUTAB® (UNIDOX SOLUTAB®)

Composition:

Active substance: doxycycline;

One tablet contains doxycycline in the form of doxycycline monohydrate 100 mg;

Excipients: microcrystalline cellulose, saccharin, low-substituted hydroxypropylcellulose, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate, lactose monohydrate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties: round, biconvex tablets ranging from light yellow–grey-yellow to brown in colour, with speckles, marked with the inscription “173” on one side and a score line on the other side.

Pharmacotherapeutic group. Antibacterials for systemic use. Tetracyclines. Doxycycline. ATC code J01AA02.

Pharmacological Properties

Pharmacodynamics

Doxycycline exerts a bacteriostatic effect; its antimicrobial action is achieved by inhibition of protein synthesis. The drug is effective against a broad spectrum of gram-positive and gram-negative bacteria and some other microorganisms.

Pharmacokinetics

Tetracyclines are readily absorbed and bind to plasma proteins. They accumulate in the liver and are excreted in bile and in biologically active form in high concentrations in urine and feces.

Doxycycline is almost completely absorbed after oral administration. Studies show that the absorption of doxycycline differs from that of some other tetracyclines and is not affected by concomitant food intake (including milk).

After a 200 mg dose, the peak serum concentration of doxycycline in healthy adult volunteers averaged 2.6 mcg/mL at 2 hours and decreased to 1.45 mcg/mL at 24 hours.

Doxycycline is a highly lipophilic substance with low affinity for calcium. It is highly stable in blood plasma. Doxycycline is not metabolized to the epi-anhydro form.

Clinical characteristics.

Indications.

Unidox Solutab**®** is indicated for the treatment of infections caused by susceptible strains of gram-positive and gram-negative microorganisms, and some other microorganisms, namely:

• Respiratory tract infections: pneumonia and other lower respiratory tract diseases caused by susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae and others. Pneumonia caused by Mycoplasma pneumoniae. Treatment of chronic bronchitis, sinusitis.
• Urinary tract infections: infections caused by susceptible strains of Klebsiella, Enterobacter, as well as Escherichia coli, Streptococcus faecalis and others.
• Sexually transmitted diseases: infections caused by Chlamydia trachomatis, including uncomplicated urethral and endocervical infections and rectal infections. Nongonococcal urethritis caused by Ureaplasma urealyticum (T-mycoplasma). Chancroid, granuloma inguinale, lymphogranuloma venereum. Unidox Solutab**®** is an alternative agent for the treatment of gonorrhea and syphilis.
• Skin infections: acne when antibiotic therapy is required.

Since the active ingredient of Unidox Solutab**®**, doxycycline, belongs to the tetracycline group of antibiotics, it can be used in infections caused by microorganisms susceptible to tetracyclines, namely:

• Ophthalmological infections: infections caused by susceptible bacteria such as gonococci, staphylococci, and Haemophilus influenzae. The infection causing trachoma is not always eliminated, as confirmed by immunofluorescence testing. For the treatment of paratrachoma, Unidox Solutab**®** can be used either as monotherapy or in combination with other medicinal products.
• Rickettsial infections: Rocky Mountain spotted fever, typhus group, Q fever, Coxiella-induced endocarditis, tick-borne fever.
• Other infections: ornithosis, brucellosis (when used in combination with streptomycin), cholera, bubonic plague, epidemic relapsing fever; tick-borne relapsing fever; tularemia; melioidosis; chloroquine-resistant tropical malaria, and acute intestinal amoebiasis (when used in combination with an amoebicide).

Unidox Solutab**®** is an alternative agent for the treatment of leptospirosis, gas gangrene, and tetanus.

Unidox Solutab**®** is indicated for prophylaxis of the following conditions: Japanese encephalitis, traveler’s diarrhea (caused by enterotoxigenic Escherichia coli), leptospirosis, malaria. Malaria prophylaxis should be conducted according to current guidelines due to the potential development of resistance.

Contraindications.

Hypersensitivity to doxycycline or tetracyclines, or to any excipient of the medicinal product.

Combination of severe renal and/or hepatic insufficiency. Severe hepatic dysfunction. Pregnancy or breastfeeding. Pediatric age under 12 years.

Interaction with other medicinal products and other forms of interaction.

Absorption of doxycycline may be reduced when administered concomitantly with antacids containing aluminum, calcium, magnesium, or other agents containing these cations, as well as with oral zinc, iron salts, or bismuth preparations. Administration of doxycycline together with such agents should be separated as much as possible in time.

Activated charcoal and ion-exchange resins (cholestyramine) may reduce doxycycline absorption. Therefore, these medicinal products should be administered 2–3 hours before taking doxycycline.

Quinapril may reduce the rate of doxycycline absorption due to the high magnesium content in quinapril tablets.

Medicinal products that increase gastric acidity may negatively affect the absorption of tetracyclines, which dissolve better in acidic environments than in alkaline environments.

Bacteriostatic agents may interfere with the bactericidal action of penicillin; therefore, concomitant use of doxycycline with penicillin is not recommended.

There have been reports of prolonged prothrombin time in patients receiving warfarin and doxycycline. Tetracyclines reduce plasma prothrombin activity; therefore, a reduction in anticoagulant dosage may be necessary.

When used concomitantly with barbiturates, carbamazepine, phenytoin, primidone, or phenylhydantoin, the half-life of doxycycline may be reduced. Therefore, consideration should be given to increasing the daily dose of Unidox Solutab**®**.

Alcohol may reduce the half-life of doxycycline.

There have been reports of several cases of pregnancy and breakthrough bleeding during concomitant use of doxycycline and oral contraceptives.

Doxycycline may increase plasma concentrations of cyclosporine. Concomitant use of these agents should be closely monitored.

Doxycycline potentiates the hypoglycemic effect of sulfonylurea derivatives. Blood glucose levels should be carefully monitored during concomitant use of these medicinal products, and doses of sulfonylurea derivatives should be reduced if necessary.

If doxycycline is administered shortly before, during, or after a course of retinoids (e.g., acitretin, isotretinoin), there is a risk that potentiation between the agents may cause reversible intracranial hypertension. Therefore, concomitant use of these medicinal products should be avoided.

Concomitant use with methotrexate may lead to increased toxicity of the latter.

Concomitant treatment with digoxin or digoxin derivatives poses a risk of increased digoxin plasma concentration, which may lead to digoxin intoxication (nausea, vomiting, dizziness, fatigue, cardiac arrhythmias).

Concomitant use of theophylline and doxycycline increases the risk of gastrointestinal adverse effects.

Tetracyclines may inhibit the metabolism of ergot alkaloids in the liver (individual cases of ergotism are possible).

Renal toxicity with fatal outcome has been reported with concomitant use of tetracyclines and methoxyflurane (see section "Special precautions").

Concomitant use of isotretinoin or other systemic retinoids with doxycycline should be avoided. Each of these medicinal products, when used separately, may in some cases cause reversible increased intracranial pressure (pseudotumor cerebri) (see section "Special precautions").

Laboratory parameters.

False elevation of urinary catecholamine levels may occur due to interference with fluorescent tests. Tetracyclines interfere with glucose tests in urine.

Glucose tests in urine may yield false-positive results when using copper sulfate-based methods (Benedict’s test). Glucose tests in urine using glucose oxidase reagents may yield false-negative results.

Special precautions for use.

Cross-resistance and cross-susceptibility to other tetracycline antibiotics may occur.

Patients with hepatic impairment. Tetracyclines may be hepatotoxic, especially when administered in high doses or concomitantly with other hepatotoxic medicinal products, or in the presence of pre-existing hepatic or renal impairment. Junidox Solutab**®** should be used with caution in patients with impaired liver function (see section "Contraindications") and in those receiving potentially hepatotoxic drugs concomitantly. Rare cases of abnormal liver function tests have been reported during both oral and parenteral administration of tetracyclines, including doxycycline.

Patients with renal impairment. In patients with normal renal function, renal excretion of doxycycline is approximately 40% over 72 hours. This may decrease to 1–5% over 72 hours in patients with severe renal impairment (creatinine clearance below 10 mL/min). Studies have shown no significant difference in the serum half-life of doxycycline between patients with normal renal function and those with severe renal impairment. Hemodialysis does not affect the serum half-life of doxycycline.

The anti-anabolic effect of tetracyclines may increase blood urea levels. Studies have shown that this anti-anabolic effect does not occur when administered to patients with renal impairment. However, worsening of azotemia may occur in patients with impaired renal function. Tetracyclines should be used with caution in patients with moderate to severe renal impairment under medical supervision.

Serious skin reactions. Serious skin reactions such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported with the use of doxycycline (see section "Adverse reactions"). If serious skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy initiated.

Photosensitivity. This effect manifests as an exaggerated response to sunlight and has been observed in some patients receiving tetracyclines, including doxycycline. Patients who are to be exposed to sunlight or ultraviolet radiation should be informed of the possibility of this reaction and advised to discontinue treatment at the first sign of erythema.

Cases of photo-onycholysis have been reported in patients taking doxycycline (see section "Adverse reactions"). During treatment with doxycycline, exposure to sunlight and use of tanning beds should be avoided.

Overgrowth of microorganisms. Treatment with doxycycline may lead to overgrowth of non-susceptible microorganisms on the skin or mucous membranes (genital tract, oral cavity, and gastrointestinal tract) due to selection (e.g., Candida) (see section "Adverse reactions"). Any emerging infections should be treated appropriately.

Cases of pseudomembranous colitis have been reported in patients receiving antibacterial agents, including doxycycline. The severity of the condition ranged from mild to life-threatening. It is important to consider the possibility of pseudomembranous colitis and staphylococcal enteritis in patients who develop diarrhea as a consequence of antibacterial therapy. Depending on the diagnosis, vancomycin or teicoplanin should be used to treat pseudomembranous colitis, and cloxacillin for staphylococcal enteritis. In such cases, intestinal peristalsis inhibitors should not be used.

The use of antibacterial agents, including doxycycline, has been associated with the development of Clostridium difficile-associated diarrhea (CDAD), with severity ranging from mild to fatal colitis. Antibacterial agents alter the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD.

Toxin-producing strains of C. difficile may increase morbidity and mortality, as such infections are resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in patients presenting with diarrhea following antibacterial therapy. Careful medical history is essential, as cases of CDAD have been reported up to two months after completion of antibacterial therapy.

Esophagitis. Esophagitis and esophageal ulceration have been reported with the use of tetracyclines, including doxycycline, in tablet and capsule forms. Most patients with such complaints had taken the medication immediately before bedtime or with insufficient fluid. This medicinal product should be taken with a large amount of liquid (water) to prevent esophageal irritation and ulceration (see section "Dosage and administration"). Tablets should be swallowed while sitting or standing.

Bulging of the fontanelle in newborns and benign intracranial hypertension in children and adults have been reported during full therapeutic doses of tetracyclines. These conditions resolve rapidly upon discontinuation of the drug.

Benign intracranial hypertension. Bulging of the fontanelle has been reported in infants receiving tetracycline therapy. Benign intracranial hypertension (pseudotumor cerebri) has been associated with the use of tetracyclines, including doxycycline. Although benign intracranial hypertension is usually transient, cases of irreversible vision loss due to benign intracranial hypertension have been reported with tetracycline use, including doxycycline. If visual disturbances occur during treatment, urgent ophthalmological evaluation is required. Since intracranial pressure may remain elevated for several weeks after discontinuation of the drug, patients should be monitored until their condition stabilizes. Concomitant use of isotretinoin or other systemic retinoids with doxycycline should be avoided, as isotretinoin is also known to cause benign intracranial hypertension (see section "Interaction with other medicinal products and other forms of interaction").

Porphyria. Rare cases of porphyria have been reported in patients receiving tetracyclines.

Sexually transmitted diseases. During treatment of sexually transmitted diseases, appropriate diagnostic tests, including dark-field microscopy, should be performed if coexisting syphilis is suspected. Serological tests should be conducted monthly for at least four months in such cases.

Infections caused by β-hemolytic streptococci. For infections caused by group A β-hemolytic streptococci, treatment should last at least 10 days.

Myasthenia gravis. Due to the potential for weak neuromuscular blockade, the drug should be used with caution in patients with myasthenia gravis.

Systemic lupus erythematosus. The use of tetracyclines may exacerbate systemic lupus erythematosus.

Methoxyflurane. Methoxyflurane should be used with caution when administered concomitantly with tetracyclines.

Jarisch-Herxheimer reaction. In some patients with spirochetal infections, a Jarisch-Herxheimer reaction may occur immediately after initiation of doxycycline therapy. Patients should be informed that this reaction is a consequence of antibiotic treatment of spirochetal infections.

Tetracyclines may affect blood coagulation (prolongation of prothrombin time). Therefore, tetracyclines should be used with particular caution in patients with coagulation disorders (see section "Interaction with other medicinal products and other forms of interaction").

During prolonged treatment, periodic laboratory monitoring of organ and system function should be performed, including hematopoietic system, renal and liver function tests. Treatment should be discontinued if abnormalities are detected.

Long-term use of tetracyclines has been reported to cause a brown-black discoloration of the thyroid gland, observed microscopically. No impairment of thyroid function has been documented.

Prolonged use of tetracyclines may lead to vitamin B deficiency due to elimination of vitamin B-producing bacteria.

Increased excretion of ascorbic acid and folic acid has been observed during tetracycline therapy, although this is usually not clinically significant.

The product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this product.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated during pregnancy. Risks associated with tetracycline use during pregnancy are primarily due to their effects on the development of teeth, bones, and skeleton (see section "Pediatric population" regarding use during tooth development).

There is an increased risk of liver damage during tetracycline use in pregnancy.

Breastfeeding

Tetracyclines pass into breast milk; therefore, the use of this product is contraindicated during breastfeeding (see section "Pediatric population" regarding use during tooth development).

Ability to affect reaction speed when driving or operating machinery.

The effect of doxycycline on the ability to drive or operate machinery has not been studied. If adverse reactions such as arterial hypotension, dizziness, tinnitus, blurred vision, scotoma, diplopia, or prolonged vision loss occur, patients should refrain from driving or operating machinery (see section "Adverse reactions").

Method of Administration and Dosage

Junidox Solutab**®** is intended for oral use only.

Add the tablet to a glass of water and stir well until a uniform mixture is obtained. The mixture should be taken immediately. The medicine should be taken while sitting or standing, well before going to bed, to reduce the risk of esophagitis or esophageal ulceration. The mixture is best taken with food.

The score line on the tablet is not intended for dividing the tablet into equal doses; it is for aesthetic purposes only.

Adults. The usual dose of Junidox Solutab**®** for adults in the treatment of acute infections is 200 mg on the first day of treatment (either as a single dose or 100 mg every 12 hours), followed by 100 mg daily thereafter. In the treatment of severe infections, the drug should be administered at a dose of 200 mg daily throughout the entire treatment period.

Exceeding the recommended dose may increase the frequency of adverse reactions. Therapy should be continued for 24–48 hours after the symptoms of the disease and fever have disappeared.

In streptococcal infections, treatment should be continued for 10 days to prevent the development of rheumatic fever or glomerulonephritis.

Children. For children aged 12 years and older with body weight below 45 kg, the recommended dose is 4.4 mg/kg body weight (on the first day of treatment, the recommended dose may be administered as a single dose or in two divided doses); in subsequent days, the dose is 2.2 mg/kg body weight (as a single or two divided doses); in more severe infections, the dose may be increased up to 4.4 mg/kg body weight.

Children with body weight above 45 kg should receive the standard adult dose.

Use of the drug in the treatment of specific infections.

• Acne: the recommended dose is 50 mg daily with food (including liquids) for 6–12 weeks.
• Sexually transmitted diseases: for the treatment of uncomplicated gonococcal infections (except anorectal infections in males), uncomplicated urethral and endocervical infections, rectal infections caused by Chlamydia trachomatis, and nongonococcal urethritis caused by Ureaplasma urealyticum, the recommended dose is 100 mg twice daily for 7 days.

For the treatment of acute epididymo-orchitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae, the drug should be administered at 100 mg twice daily for 10 days.

For the treatment of primary and secondary syphilis, the recommended dose for patients without confirmed pregnancy and with penicillin allergy is 200 mg orally twice daily for 2 weeks (as an alternative to penicillin therapy).

• Epidemic relapsing fever, tick-borne relapsing fever: the recommended dose is 100–200 mg as a single dose, depending on the severity of the disease.
• Chloroquine-resistant tropical malaria: the recommended dose is 200 mg daily for at least 7 days due to the potential severity of the infection.

Always, as adjunctive therapy to Junidox Solutab**®**, a fast-acting schizonticide (e.g., quinine) should be used, with dosage varying on a case-by-case basis due to the potential severity of the infection.

• Malaria prophylaxis: the recommended dose for adults is 100 mg daily. For children aged 12 years, the recommended dose is 2 mg/kg daily, up to a maximum of 100 mg daily. Prophylaxis may be initiated 1–2 days before travel to a malaria-endemic region. Prophylactic use should continue daily during the stay in the malaria-endemic region and for 4 weeks after leaving the region. Current malaria treatment guidelines should also be considered.
• Prophylaxis of Japanese encephalitis: the recommended dose is 200 mg as a single dose.
• Prophylaxis of traveler’s diarrhea in adults: the recommended dose is 200 mg on the first day of travel (administered as a single 200 mg dose or 100 mg every 12 hours), followed by 100 mg daily for the subsequent days of travel. Information on use beyond 21 days for prophylaxis is lacking.
• Prophylaxis of leptospirosis: the recommended dose is 200 mg once weekly throughout the stay in a leptospirosis-endemic region and 200 mg at the end of the trip. Information on use beyond 21 days for prophylaxis is lacking.
• Use in elderly patients: the drug can be used at standard doses without special precautions. Dose adjustment is not necessary in renal impairment. Junidox Solutab**®** may be the drug of choice for elderly patients, as its use is less associated with esophageal irritation and ulceration.
• Use in patients with hepatic impairment – see section "Special Warnings and Precautions for Use".
• Use in patients with renal impairment – studies have shown that administration of the drug at recommended doses does not lead to antibiotic accumulation in these patients (see section "Special Warnings and Precautions for Use").

Children. Junidox Solutab**®** is contraindicated in children under 12 years of age. Like other tetracyclines, Junidox Solutab**®** forms stable calcium complexes in any calcifying tissue. Decreased growth of the tibia has been observed in premature infants receiving tetracyclines orally at 25 mg/kg every 6 hours. This adverse reaction is reversible upon discontinuation of the drug. Use of tetracyclines during tooth development (second half of pregnancy, infants, and children up to 12 years of age) may cause permanent tooth discoloration (yellow-brown-gray). This adverse effect is more common with prolonged use but may also occur with repeated short courses. Hypoplasia of enamel has also been reported.

Overdose.

Acute overdose of antibiotics is rare. In case of overdose, the drug should be discontinued. Symptoms of intoxication may include liver damage, manifested by vomiting, fever attacks, jaundice, bruising, melena, azotemia, elevated transaminase levels, prolonged prothrombin time, and pancreatitis development.

Treatment of intoxication

Overdose may cause irritation and ulceration of the esophagus, accompanied by retrosternal pain, dysphagia, and esophagitis. This is due to the possibility of tablets lodging in the esophagus. In such cases, drink up to 200 ml of water (125 ml for children). Inducing vomiting is not recommended to avoid further esophageal irritation. Administration of activated charcoal and a laxative may be sufficient to reduce absorption. Hemodialysis does not affect the elimination of doxycycline. Treatment should be symptomatic with monitoring of fluid and electrolyte balance.

Adverse Reactions

Adverse reactions are listed below by system organ classes and frequency according to MedDRA. Frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).

The following adverse reactions have been observed in patients treated with tetracyclines, including doxycycline.

Infections and infestations

Common: vaginitis.

Rare: candidiasis.

Blood and lymphatic system disorders

Rare: haemolytic anaemia, thrombocytopenia, neutropenia, decreased prothrombin levels, eosinophilia, leukocytosis, lymphocytopenia, lymphadenopathy, presence of atypical lymphocytes, and toxic granulation of granulocytes.

Not known: prolonged prothrombin time (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Immune system disorders

Common: hypersensitivity reactions, including anaphylactic shock, anaphylaxis, anaphylactoid reactions, Henoch-Schönlein purpura, angioneurotic oedema; hypotension; pericarditis; exacerbation of systemic lupus erythematosus; dyspnoea; serum sickness; peripheral oedema; tachycardia; urticaria.

Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Jarisch-Herxheimer reaction (when treating spirochetal infections with doxycycline).

Endocrine system disorders

Rare: brown-black microscopic pigmentation of thyroid tissue (with long-term use of tetracyclines, see section "Special warnings and precautions for use") — without impairment of thyroid function.

Metabolism and nutrition disorders

Rare: porphyria, anorexia, decreased appetite.

Nervous system disorders

Common: headache.

Rare: anxiety, paraesthesia, anxiety, benign intracranial hypertension (pseudotumor cerebri), bulging of the fontanelle, disturbances or loss of olfactory and taste sensation, in some cases partially irreversible.

Very rare: convulsions, depression, hallucinations.

* Bulging of the fontanelle in neonates and benign intracranial hypertension in children and adults have been reported during full therapeutic doses of tetracyclines. Benign intracranial hypertension associated with tetracycline use, including doxycycline, has been observed in adults and older children, manifesting with meningeal irritation and papilledema. Symptoms of benign intracranial hypertension may include headache, nausea, tinnitus, dizziness, blurred vision, hallucinations, scotoma, and diplopia. These symptoms usually resolve within several days or weeks after discontinuation of therapy. Cases of irreversible vision loss have been reported.

Ear and labyrinth disorders

Rare: tinnitus, vertigo.

Vascular disorders

Rare: hot flushes.

Gastrointestinal disorders

Gastrointestinal adverse reactions are usually mild and do not require discontinuation of treatment.

Common: nausea, vomiting, black tongue.

Uncommon: dyspepsia (heartburn/gastritis).

Rare: abdominal pain, dysphagia, enterocolitis (including staphylococcal enteritis), inflammatory lesions (with overgrowth of Candida) in the anogenital area, anal pruritus, pancreatitis, pseudomembranous colitis (with overgrowth of Clostridioides difficile, see "Special warnings and precautions for use"), diarrhoea, glossitis, stomatitis, suppression of vitamin B-synthesizing bacteria, oesophagitis and oesophageal ulceration (see section "Special warnings and precautions for use").

Not known: tooth discoloration (reversible surface discoloration of permanent teeth has been reported with doxycycline use, but frequency cannot be estimated from available data), hypoplasia of tooth enamel (mainly after prolonged use).

Hepatobiliary disorders

Rare: hepatotoxicity with transient elevation of liver enzymes, hepatitis, jaundice, hepatic failure, and liver function abnormalities.

Skin and subcutaneous tissue disorders

Common: skin rashes, including maculopapular and erythematous rashes, skin photosensitivity reactions (see "Special warnings and precautions for use").

Rare: exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photo-onycholysis, hyperpigmentation of the skin (with chronic doxycycline use).

Musculoskeletal and connective tissue disorders

Common: disorders of bone and tooth development (brittle bones, irreversible tooth discoloration).

Rare: arthralgia, myalgia.

Renal and urinary disorders

Uncommon: haematuria.

Rare: increased blood urea levels.

Very rare: renal impairment, such as interstitial nephritis, acute renal failure, anuria.

Not known: worsening of azotemia in patients with renal insufficiency. Fanconi-like syndrome, including albuminuria, glucosuria, aminoaciduria, hypophosphatemia, hypokalemia, and tubular renal acidosis.

Shelf life. 5 years.

Storage conditions. Keep out of the reach of children. Store at temperatures not exceeding 25°C.

Packaging. 10 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Astellas Pharma Europe B.V., the Netherlands.

Manufacturer's address. Hogemaat 2, 7942 JG Meppel, the Netherlands.

Marketing Authorisation Holder.

CHEPLAPHARM Arzneimittel GmbH

Address of Marketing Authorisation Holder.

Ziegelhof 24, 17489 Greifswald, Germany