Cefditoren Pivoxil Dry Powder Suspension

Each 5 ml of reconstituted suspension contains :

Cefditoren Pivoxil equivalent to Cefditoren 100 mg

Excipients q.s.

Dry powder for Suspension

4.1 Therapeutic indication

Cefditoren pivoxil is indicated for the treatment of mild to moderate infections in children (2 months to 12 years of age) which are caused by susceptible strains of the designated microorganisms in the conditions listed below :

• Acute bacterial exacerbation of chronic bronchitis
• Community-acquired pneumonia
• Pharyngitis/tonsillitis
• Acute sinusitis
• Uncomplicated skin and skin-structure infections

4.2 Posology and method of administration

Recommended doses in children (2 months to 12 years of age)

For children with pneumonia, otitis media or sinusitis In general, 3 mg/kg/dose, 3 times a day, after meals. The dosage may be increased up to 6 mg/kg/dose as needed, but should not exceed 200 mg, 3 times a day (600 mg / day). For children with diseases other than above diseases In general, 3 mg/kg/dose, 3 times a day, after meals. The dosage may be adjusted according to the disease or the patient's age and symptoms, but should not exceed 200 mg, 3 times a day (600 mg /day).

Direction for reconstitution

Shake the bottle well to loosen the granules. Add freshly boiled and cooled water up to the ring mark on the bottle & shake well. Add more water if necessary to adjust the volume up to the ring mark. This makes 30 ml of suspension. The reconstituted suspension should be consumed within 7 days of preparation.

4.3 Contraindications

• Patients with known allergy to the cephalosporin class of antibiotics or any of its components
• Patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of Cefditoren causes renal excretion of carnitine.

4.4 Special warnings and precautions for use

• Before therapy with cefditoren pivoxil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefditoren pivoxil, other cephalosporins, penicillins, or other drugs.
• If cefditoren pivoxil is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among β-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.
• If an allergic reaction to cefditoren pivoxil occurs, the drug should be discontinued. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
• Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefditoren pivoxil, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
• Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibioticassociated colitis.
• After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
• Prescribing cefditoren pivoxil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria
• Cefditoren pivoxil is not recommended when prolonged antibiotic treatment is necessary, since other pivalate-containing compounds have caused clinical manifestations of carnitine deficiency when used over a period of months. No clinical effects of carnitine decrease have been associated with short-term treatment.
• Community-acquired pneumonia clinical trials demonstrated no adverse events attributable to decrease in serum carnitine concentrations. However, some sub-populations (e.g., patients with renal impairment, patients with decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during cefditoren pivoxil therapy.
• As with other antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.
• Prothrombin time should be monitored in patients at risk and exogenous vitamin K should be administered as indicated.

4.5 Drugs interactions

Oral Contraceptives

Multiple doses of cefditoren pivoxil had no effect on the pharmacokinetics of ethinyl estradiol, the estrogenic component in most oral contraceptives.

Antacids

Co-administration of a single dose of an antacid which contained both magnesium (800 mg) and aluminum (900 mg) hydroxides reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 14% decrease in mean Cmax and an 11% decrease in mean AUC. Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with antacids.

H2-Receptor Antagonists

Co-administration of a single dose of intravenously administered famotidine (20 mg) reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 27% decrease in mean Cmax and a 22% decrease in mean AUC. Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with H2 receptor antagonists.

Probenecid

As with other β-lactam antibiotics, co-administration of probenecid with cefditoren pivoxil resulted in an increase in the plasma exposure of cefditoren, with a 49% increase in mean Cmax, a 122% increase in mean AUC, and a 53% increase in t1/2.

4.6 Use in special populations

Pregnancy

Cefditoren pivoxil was not teratogenic up to the highest doses tested in rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Breast-feeding

Because many drugs are excreted in human breast milk, caution should be exercised when cefditoren pivoxil is administered to nursing women.

4.7 Effects on ability to drive and use machines

Cefditoren has no or negligible influence on the ability to drive or use machines. However, cefditoren may cause side effects influencing the capacity of reaction and the ability to drive and use machines.

4.8 Undesirable effects

As a result of post-marketing survey of cefditoren granules, total 5,821 clinical cases were reported from 875 facilities in Japan. The number of side effects was 136 cases (2.34%), and the number of adverse reactions occurred was 146 cases. The main adverse reactions were 121 cases (2.08%) of digestive tract disorders (diarrhea, loose stools, etc.), 10 cases (0.17%) of skin and skin structure disorders (rash, urticaria).

Serious side effects (<0.1%)

• Shock and anaphylaxis, severe colitis (as pseudomembranous colitis), toxic epidermal necrolysis (TEN), stevens-johnson syndrome, interstitial pneumonia, liver function disorder, severe kidney injury, agranulocytosis, hemolytic anemia if any of these disorders are recognized, stop administration immediately and take appropriate measures.
• Since hypoglycemia (frequency unknown) associated with hypocarnitinemia may be seen in cases in which antibiotics having pivoxil groups are administered to children (especially infants), hypoglycemic symptoms such as convulsions and disturbances of consciousness are observed. If so, discontinue administration and take appropriate measures

Other side effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Information on cefditoren pivoxil overdosage in humans is not available. However, with other β-lactam antibiotics, adverse effects following overdosage have included nausea, vomiting, epigastric distress, diarrhea, and convulsions. Hemodialysis may aid in the removal of cefditoren from the body, particularly if renal function is compromised (30% reduction of plasma concentrations following 4 hours of hemodialysis).

The stomach should be emptied by aspiration and gastric lavage. Vital parameters should be managed symptomatically and institute supportive measures as required.

5.1 Mechanism of action

Cefditoren is bactericidal in nature and its activity results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs). It has high affinity for penicillin binding protein (PBP) of various bacteria

5.2 Pharmacodynamic properties

Antibacterial activity Cefditoren pivoxil is metabolized into cefditoren on absorption in the intestinal wall and shows its antibacterial activity. Cefditoren exerts broad spectrum antibacterial activity in vitro against gram-positive and gram-negative bacteria. Especially it showed strong antibacterial activity against gram-positive bacteria such as Staphylococcus sp., Streptococcus sp. and Streptococcus pneumoniae, and gram-negative bacteria such as Escherichia coli, Moraxella (Branhamella) catarrhalis, Klebsiella sp., Proteus sp. and Haemophilus influenzae, and against anaerobic bacteria such as Peptostreptococcus sp., Propionibacterium acnes, Bacteroides sp. and Prevotella sp. Cefditoren also showed antibacterial activity against β-lactamase-non producing ampicillin resistant Haemophilus influenzae (BLNAR). In vitro, cefditoren was stable against β-lactamases produced by various bacteria, and showed strong antibacterial activity against β-lactamase-producing strains

5.3 Pharmacokinetic properties

Absorption and distribution

Following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases.

Serum concentration and pharmacokinetic parameters of cefditoren were as shown in Table 1 when doses of 3 mg - 6 mg/kg were orally administered to pediatric patients with normal renal function. Table 1 : Pharmacokinetic parameters of normal pediatric patients with renal function.

After absorption cefditoren is distributed to different body fluids and tissues e.g. sputum, tonsil tissue, maxillary sinus mucosa, skin tissue, tooth extraction wound etc. Protein binding: The binding rate with human serum protein measured by ultrafiltration was 91.5% at a concentration of 25 μg / mL (in vitro).

Metabolism / Excretion

Cefditoren pivoxil undergoes metabolism upon absorption and becomes cefditoren and pivalic acid with antimicrobial activity. Pivalic acid undergoes carnitine conjugation and is excreted in the urine as pivaloylcarnitine. Cefditoren is excreted largely in urine and bile without much metabolism. Urinary excretion rate (0 to 8 hours) as cefditoren was about 20% and 17%, respectively, when orally administered 3 mg / kg, 6 mg / kg once or twice to pediatric patients with normal renal function. Urinary excretion rate decreased as the extent of impairment of renal function increased, and a delay of excretion was observed.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Zostum-O 100 Dry Suspension contains cefditoren pivoxil, a semi-synthetic cephalosporin antibiotic for oral administration. It is a prodrug which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active cefditoren

Chemical name : 2, 2-Dimethylpropanoyloxymethyl (6R, 7R)-7-[(Z)-2- (2-aminothiazol-4-yl)-2- (methoxyimino) acetylamino]-3-[(1Z)-2-(4-methylthiazol-5-yl) ethenyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylate.

8.1 Incompatibilities

Not Applicable

8.2 Shelf Life

Refer on the pack.

8.3 Packaging Information

A bottle of 12 g / 30 ml

8.4 Storage and handing Instructions

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

Parents or caregivers should be counselled that antibacterial drugs including Zostum-O 100 Suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

When Zostum-O 100 Suspension is prescribed to treat a bacterial infection, patients/ parents or caregivers should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zostum-O 100 Suspension or other antibacterial drugs in the future

Zostum-O 100 Suspension (cefditoren pivoxil) should be taken with meals to enhance absorption.

It is not recommended that Zostum-O 100 Suspension be taken concomitantly with antacids or other drugs taken to reduce stomach acids.

15 October 2022

Nicoumalone Tablets IP 1 mg/2mg/3 mg/4 mg

Each uncoated tablet contains

Nicoumalone IP 1mg/2 mg/3 mg/4 mg

Excipients q.s

Tablets for oral administration.

1 mg/2 mg/3 mg/4 mg

Therapeutic indication

For the prevention and treatment of thromboembolic diseases such as venous thrombosis, atrial fibrillation with embolization, pulmonary embolism and as an adjunct in the treatment of coronary occlusion.

Posology and method of administration

Posology

General target population

Sensitivity to anticoagulants varies from patient to patient and may also fluctuate during the course of treatment. Therefore, it is essential to perform regular testing of prothrombin time (PT)/International Normalised Ratio (INR) and to adjust the patient's dosage accordingly. If this is not possible, Artiflo should not be used. Artiflo should be given in a single oral dose.

Initial dosage:

The dosingof Artiflo must be individualised. If the PT/INR value is within the normal range before starting treatment, the following dosage schedule is recommended:

• The usual starting dose is between 2 mg/day to 4 mg/day without administration of a loading dose.
• Treatment may also be initiated with a loading dose regimen, usually 6 mg on the first day followed by 4 mg on the second day.

If the initial thromboplastin time is abnormal, treatment should be instituted with caution.

Elderly patients (≥65), patients with liver disease or severe heart failure with hepatic congestion or malnourished patients may require lower doses during treatment initiation and maintenance. Measurement of the thromboplastin time should be carried out daily in hospital starting from second or third dose of Artiflo and up to the time when the coagulation status is stabilized within the target range. The interval between tests can later be extended, depending on the stability of PT/INR results. Blood samples for laboratory tests should always be taken at the same time of day.

Maintenance therapy and coagulation tests

The maintenance dose of Artiflo varies from patient to patient and must be checked individually on the basis of PT/INR values. PT/INR should be assessed at regular intervals, i.e. at least once a month. The maintenance dose generally lies between 1 to 8mg daily depending on the individual patient, the underlying disease, clinical indication and desired intensity of anticoagulation.

Depending on the clinical indication, the optimal intensity of anticoagulation or therapeutic range to be aimed at generally lies between INR values of 2.0 and 3.5 (see Table 1). Higher INR values up to 4.5 may be required in individual cases. Table 1 Recommended INR* for Oral Anti-coagulant Therapy

*The PT, which reflects the reduction of Vitamin K dependent clotting factors VII, X and II, is dependent on the responsiveness of the thrombosplastin used for PT-testing. The responsiveness of the respective local thromboplastin compared to World Health Organisation international reference preparations is reflected by its International Sensitivity Index (ISI). The “International Normalised Ratio” (INR) was introduced for the purpose of standardisation of the PT. The INR is the ratio of the patient's anticoagulated plasma PT to the normal plasma PT using the same thromboplastin in the same test system raised to the power of a value defined by the International Sensitivity Index.

Treatment discontinuation

Generally, after withdrawal of Artiflo, there is usually no danger of reactive hypercoagulability and therefore it is not necessary to give gradually diminishing doses. However, in extremely rare cases, in some high risk patients (e.g. after myocardial infarction), withdrawal should be gradual.

Missed dose

The anticoagulant effect of Artiflo persists beyond 24 hours. If the patient forgets to take the prescribed dose of Artiflo at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not double the daily dose to make up for a missed dose, but should refer back to his or her doctor.

Conversion from heparin therapy

In clinical situations which require rapid anticoagulation, initial treatment with heparin is preferred since the anticoagulant effect of Artiflo is delayed. Conversion to Artiflo may begin concomitantly with heparin therapy or may be delayed depending on the clinical situation. To ensure continuous anticoagulation, it is advisable to continue to prescribe full dose heparin therapy for at least 4 days after initiation of Artiflo and to continue heparin therapy until the INR has been in the target range on at least two consecutive days. During the transition phase close monitoring of anticoagulation is necessary.

Treatment during dentistry and surgery

Patients on Artiflo, who undergo surgical or invasive procedures require close surveillance of their coagulation status. Under certain conditions, e.g. when the operation site is limited and accessible to permit effective use of local procedures for haemostasis, dental and minor surgical procedures may be performed during continued anticoagulation, without undue risk of haemorrhage. The decision to discontinue Artiflo, even for a short period of time, should carefully consider individual risks and benefits. The introduction of bridging anticoagulant treatment, e.g. with heparin should be based on careful assessment of the expected risks of thromboembolism and bleeding.

Special populations

Renal impairment

Artiflo is contraindicated in patients with severe renal impairment due to an increased risk of haemorrhage. Caution should be exercised in patients with mild to moderate renal impairment.

Hepatic impairment

Artiflo is contraindicated in patients with severe hepatic impairment due to an increased risk of haemorrhage. Caution should be exercised in patients with mild to moderate hepatic impairment.

Paediatric population

Experience with oral anticoagulants including nicoumalone in children remains limited. Caution and more frequent monitoring of PT/INR is recommended.

Elderly

A dose lower than the recommended adult dose may be sufficient in elderly patients. caution and more frequent monitoring of PT/INR is recommended.

Method of administration

The daily dosage should always be taken at the same time of day. The tablet should be swallowed whole with a glass of water.

Contraindications

• Known hypersensitivity to nicoumalone and related coumarin derivatives or to any of the excipients of Artiflo.
• Pregnancy
• Patients unable to co-operate and who are unsupervised (e.g. unsupervised senile patients, alcoholics and patients with psychiatric disorders).

Artiflo is also contraindicated in conditions where the risk of haemorrhage is greater than the possible clinical benefit, e.g.

• Haemorrhagic diathesis or haemorrhagic blood dyscrasias
• Shortly before or after surgical interventionon the central nervous system as well as the eyes and traumatising surgery involving extensive exposure of the tissues
• Peptic ulcers or haemorrhage in the gastro-intestinal tract, urogenital tract or respiratory system; cerebrovascular haemorrhages; acute pericarditis; pericardial effusion; infective endocarditis
• Severe hypertension (due to occult risks)
• Severe hepatic impairment
• Severe renal impairment
• Increased fibrinolytic activity as encountered after operations on the lung, prostate or uterus etc.

Special warnings and precautions for use

Hepatic impairment

Caution should be exercised in patients with mild to moderate hepatic impairment since the synthesis of blood coagulation factors may be impaired or there may be an underlying platelet dysfunction.

Renal impairment

Due to the possibility of accumulation of metabolites in impaired renal function, caution should be exercised in patients with mild to moderate renal impairment.

Heart failure

In severe heart failure, a very cautious dosage schedule must be adopted, since hepatic congestion may reduce the activation of gamma-carboxylation of coagulation factors. However, with reversal of the hepatic congestion, it may be necessary to raise the dosage.

Haematological

Caution should be exercised in patients with known or suspected (e.g. abnormal bleeding after injury) protein C or protein S deficiency.

Calciphylaxis

Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality. The condition is mainly observed in patients with end-stage renal disease on dialysis or in patients with known risk factors such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia or hypoalbuminaemia. Rare cases of calciphylaxis have been reported in patients taking vitamin K antagonists including Artiflo also in the absence of renal disease. In case calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with Artiflo.

Hemorrhage

Artiflo can cause major (including hemorrhagic and hypovolemic shock) or fatal bleeding. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥ 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs, Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy.

Special populations

In paediatric and elderly patients (≥65 years), caution and more frequent monitoring of PT/INR is recommended (Posology and method of administration and Pharmacokinetic properties).

Miscellaneous

Strict medical supervision should be given in cases where the disease or condition may reduce the protein binding of Artiflo (e.g. thyrotoxicosis, tumours, renal disease, infections and inflammation). Disorders affecting gastro-intestinal absorption may alter the anticoagulant activity of Artiflo. During treatment with anticoagulants, intramuscular injections may cause haematomas and should be avoided. Subcutaneous and intravenous injections may be given without such complications. Meticulous care should be taken where it is necessary to shorten the PT/INR (thromboplastin time) for diagnostic or therapeutic procedures (e.g. angiography, lumbar puncture, minor surgery, tooth extractions etc.). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.

Interaction with other medicinal products and other forms of interaction

There are many possible interactions between coumarins and other drugs; those of clinical relevance are given below. Many of these are isolated reports only or have been reported with warfarin rather than nicoumalone; for completeness, all have been included. The mechanisms of these interactions include disturbances of absorption, inhibition or induction of the metabolising enzyme system (mainly CYP2C9), and reduced availability of vitamin K1, necessary for gamma-carboxylation of prothrombin–complex factors. It is important to note that some drugs may interact by more than one mechanism. Every form of therapy may involve the risk of an interaction, although not all will be significant. Thus, careful surveillance is important and frequent coagulation tests (e.g. twice weekly) should be carried out when initially prescribing any drug in combination with Artiflo, or when withdrawing a concomitantly administered drug. Interactions resulting in concomitant use not being recommended The following drugs potentiate the anticoagulant activity of nicoumalone and/or alter haemostasis and thereby increase the risk of haemorrhage: Drugs altering haemostasis may potentiate the anticoagulant activity of Artiflo and thereby increase the risk of haemorrhage. Consequently, Artiflo should not be prescribed with such drugs, which include:

• heparin (including LMWH) (except in situations which require rapid anticoagulations); • antibiotics (e.g. clindamycin);
• platelet-aggregation inhibitors (e.g. dipyridamole, clopidogrel), salicyclic acid and its derivatives, (e.g. acetylsalicylic acid, para-aminosalicylic acid, diflunisal);
• clopidogrel, ticlopidine, phenylbutazone or other pyrazolone derivatives (e.g. sulfinpyrazone), and other non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors (e.g. celecoxib), high dose IV methylprednisolone. Increased INR has been reported in patients taking glucosamine and oral vitamin K antagonists. Patients treated with oral vitamin K antagonists should therefore be closely monitored at the time of initiation or termination of glucosamine therapy. The risk of gastrointestinal haemorrhage is increased if Artiflo is prescribed in combination with these substances. In the case of unavoidable concurrent use, coagulation tests should be performed more frequently.

Interactions to be considered

The anticoagulant effect may be potentiated by concomitant administration of the following drugs:

• allopurinol;
• anabolic steroids;
• androgens;
• anti-arrhythmic agents (e.g. amiodarone, quinidine);
• antibiotics:
  • broad spectrum antibiotics (e.g. amoxicillin, co-amoxiclav) macrolides (e.g. erythromycin, clarithromycin);
  • cephalosporins second and third generation;
  • metronidazole;
  • quinolones (e.g. ciprofloxacin, norfloxacin, ofloxacin);
  • tetracyclines;
  • neomycin;
  • chloramphenicol.
• imidazole derivatives, including topical administration (e.g. econazole, fluconazole, ketoconazole, miconazole);
• sulfonamides (including co-trimoxazole);
• fibrates (e.g. clofibric acid), its derivatives and structural analogues (e.g. fenofibrate, gemfibrozil);
• disulfiram;
• etacrynic acid;
• glucagon;
• oral antidiabetics (e.g. glibenclamide);
• sulphonylureas (such as tolbutamide and chlorpropamide);
• H2 antagonists (e.g. cimetidine);
• paracetamol;
• thyroid hormones (including dextrothyroxine);
• sulfinpyrazone;
• statins (e.g. atorvastatin, fluvastatin, simvastatin);
• selective serotonin re-uptake inhibitors (e.g. citalopram,fluoxetine, sertraline,paroxetine);
• tamoxifen;
• 5-fluorouracil and analogues;
• tramadol;
• proton pump inhibitors (e.g. omeprazole);
• plasminogen activators (e.g. urokinase; streptokinase and alteplase);
• thrombin inhibitors (e.g. argatroben);
• prokinetic agents (e.g. cisapride);
• antacids (e.g. magnesium hydroxide);
• viloxazine.
• Inhibitors of CYP2C9 may potentiate the anticoagulant effect of nicoumalone. The anticoagulant effect may be diminished by concomitant administration of the following drugs:
• aminoglutethimide;
• antineoplastic drugs (e.g. azathioprine, 6-mercaptopurine);
• barbiturates (e.g. Phenobarbital);
• carbamazepine;
• cholestyramine;
• griseofulvin;
• oral contraceptives;
• rifampicin;
• HIV protease inhibitors (e.g. ritonavir, nelfinavir);
• thiazide diuretics;
• St. John's Wort/Hypericum perforatum;
• Inducers of CYP2C9, CYP2C19 or CYP3A4 may diminish the anticoagulant effect of nicoumalone. Vitamin E and corticosteroids (e.g. methylprednisolone, prednisone) may diminish the anticoagulant effect of coumarin derivatives. Unpredictable effect on anticoagulation, including both increase and decrease in anticoagulant activity have been reported with the following drugs: protease inhibitors (e.g. indinavir, nelfinavir, ritonavir, saquinavir).

Effects of nicoumalone on other drugs:

During concomitant treatment with hydantoin derivatives (such as phenytoin), the serum hydantoin concentration may rise. Artiflo may potentiate the hypoglycaemic effect of sulphonylurea derivatives e.g. glibenclamide, glimepiride. Patients being treated with Artiflo (especially those suffering from hepatic dysfunction) should limit their alcohol intake, since it is not possible to predict the severity of any drug interactions, nor identify any early signs of such interactions. Cranberry juice should be avoided in patients receiving Artiflo due to a theoretical risk of enhanced anti-coagulation. Increased medical supervision and INR monitoring should be considered for any patient receiving Artiflo and regularly drinking cranberry juice. It is not known whether other cranberry products, such as capsules or concentrates, might also interact with Artiflo. Therefore, similar caution should be observed with these products.

Fertility, pregnancy and lactation

Pregnancy

Artiflo, like other coumarin derivatives, may be associated with congenital malformations of the embryo, therefore Artiflo is contra-indicated for use in pregnancy. Women of child-bearing potential should take contraceptive measures during treatment with Artiflo.

Breastfeeding

Nicoumalone passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected. However, as a precaution, the infant should be given 1mg vitamin K1 per week as a prophylactic measure. The decision to breast-feed should be carefully considered and may include coagulation tests and vitamin K status evaluation in infants before advising women to breast-feed. Women who are breast-feeding and treated with Artiflo should be carefully monitored to ensure that recommended PT/INR values are not exceeded.

Fertility

There are no data available on the use of Artiflo and its effect on fertility in humans.

Effects on ability to drive and use machines

Artiflo has no influence on the ability to drive and use machines. However, patients should be advised to keep their anticoagulant card with them.

Undesirable effects

Undesirable effects are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated reports. Haemorrhage, in various organs, is the most common side-effect associated with Artiflo; its occurrence is related to the dosage of the drug, the patient's age and the nature of the underlying disease. Fatalities have been reported. Possible sites of haemorrhage include the gastro-intestinal tract, brain, urogenital tract, uterus, liver, gall bladder and the eye. If haemorrhage occurs in a patient with a thromboplastin time within the therapeutic range, diagnosis of their condition must be clarified.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com  By reporting side effects, you can help provide more information on the safety of this medicine.

Overdose

Clinical manifestations of overdosage are unlikely with large single doses, but more likely following prolonged use of daily doses exceeding those required therapeutically.

Hospital referral is recommended for any amount of Artiflo taken above the therapeutic dose.

Symptoms:

The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdose and the duration of treatment. Haemorrhage is the prominent feature of an overdose and may occur within 1 to 5 days after ingestion. Nose-bleeds, haematemesis, haemoptysis, gastro-intestinal haemorrhage, vaginal bleeding, haematuria (with renal colic), cutaneous haemorrhages, gingival bleeding, haematomata, and bleeding into the joints or menorrhagia may be experienced.

Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains. Laboratory tests will show an extremely low Quick value (or high PT/INR value), pronounced prolongation of the recalcification time or thromboplastin time and disturbed gamma-carboxylation of factors II, VII, IX and X.

Treatment:

The necessity or desirability of the treatment by gastric lavage in addition to the activated charcoal and cholestyramine administration is controversial. The benefits of these treatments should be balanced against the risk of bleeding in each patient. Emergency and supportive

measures:

In emergency situations of severe haemorrhage, clotting factors can be returned to normal by administering fresh whole blood or fresh frozen plasma, complex concentrate or recombinant factor VIIa supplemented with vitamin K1.

Antidote:

Vitamin K1 (phytomenadione) may antagonise the inhibitory effect of Artiflo on hepatic gamma-carboxylation of the vitamin K-dependent coagulation factors within 3 to 5 hours. In cases of clinically insignificant haemorrhages, such as a brief nose-bleed or small isolated haematomas, a temporary reduction or omission of the dose of Artiflo is often sufficient. In cases of moderate to severe haemorrhage, Vitamin K1 can be given orally.

Doses of Vitamin K1 in excess of 5mg can cause resistance to further anticoagulant therapy for several days. If an anticoagulant is required, heparin may be used temporarily, although oral anticoagulant therapy should be resumed at the same time and heparin withdrawn once the therapeutic range has been reached.

In the case of life-threatening haemorrhage, intravenous transfusions of fresh frozen plasma or whole blood, complex concentrate or recombinant factor VIIa supplemented with vitamin K1 can abolish the effects of Artiflo. Artiflo should be resumed when INR is in target range in case of moderate to severe haemorrhage.

Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic, vitamin K antagonists. ATC code: B01AA07

Mechanism of action

Nicoumalone is a coumarin derivative and functions as vitamin K antagonist. Vitamin K antagonists produce their anticoagulant effect by inhibition of the vitamin K-epoxide-reductase with a subsequent reduction of the gamma-carboxylation of certain glutamic acid molecules which are located at several sites near the terminal end both of coagulation factors II (prothrombin), VII, IX, and X and of protein C or its cofactor protein S. Pharmacodynamic effects This gamma-carboxylation has a significant bearing on interaction of the aforementioned coagulation factors with Calcium ions. Without this reaction, blood clotting cannot be initiated. Clinical efficacy and safety Depending on the initial dosage, Artiflo prolongs the thromboplastin time within approximately 36 to 72 hours. Following withdrawal of Artiflo, the thromboplastin time usually reverts to normal after a few days.

Pharmacokinetic properties

Absorption

Nicoumalone, is a racemic mixture of the optical R (+) and S (-) enantiomers. Following oral administration, Artiflo is rapidly absorbed; at least 60% of the administered dose is systemically available. Peak plasma concentrations are achieved within 1 to 3 hours after a single dose of 10 mg and AUC values are proportional to the size of the dose over a dosage range of 8 to 16 mg.

No correlation between plasma concentrations of nicoumalone and the apparent prothombin levels can be established, due to the variation of plasma drug concentrations between patients.

Distribution

Over 98% of nicoumalone is protein-bound, mainly to albumin. The calculated apparent volume of distribution is 0.16-0.18 L/kg for the R(+) enantiomer and 0.22-0.34 L/kg for the S(-) enantiomer.

Biotransformation

Nicoumalone is extensively metabolised, 6- and 7-hydroxylation of both enantiomers of Nicoumalone are the major metabolites and the cytochrome P450 2C9 is the major catalyst for the formation of these four metabolites. Other enzymes involved in the metabolism of (R)-nicoumalone are CYP1A2 and CYP2C19. By reduction of the keto group two different carbinol metabolites are formed. Reduction of the nitro group results in an amino metabolite. None of these metabolites contribute to the anticoagulant activity of the parent drug in man, but they are all active in an animal model. CYP2C9-related genetic variability accounts for 14% of the inter-individual variability in nicoumalone pharmacodynamics response.

Elimination

The elimination half-life of nicoumalone from the plasma is 8 to 11 hours. The apparent plasma clearance amounts to 3.65 L/h after oral administration. The total plasma clearance of the (+) enantiomer of nicoumalone, which possesses significantly higher anticoagulant activity, is much lower than that of the S(-) enantiomer. 29% is excreted in the faeces and 60% in the urine, with less than 0.2% of the dose renally excreted being unchanged.

Elderly

Plasma drug concentrations are generally higher in patients of 70 years or over when compared with younger patients, after the same dose.

Renal impairment

No clinical pharmacokinetic information of Nicoumalone in renal impairment is available. Based on the urinary excretion of Nicoumalone, the possibility of accumulation of metabolites in impaired renal function cannot be excluded. Therefore, usage of Nicoumalone is contraindicated in patient with severe renal impairment and caution should be exercised in patients with mild to moderate renal impairment.

Hepatic impairment

No clinical pharmacokinetic information of nicoumalone in hepatic impairment is available. Based on the metabolism of nicoumalone, and possible reduced enzyme activities, CYP2C9, CYP1A2 and CYP3A4, clearance is likely to be reduced. Therefore, usage of nicoumalone is contraindicated in patients with severe hepatic impairment and caution should be exercised in patients with mild to moderate hepatic impairment.

Ethnicity

CYP2C9 enzyme systems are polymorphically expressed and the frequency of these in population differs. In Caucasians, occurrence of CYP2C9*2 and CYP2C9*3 frequencies are 12 and 8%, respectively. Patients with one or more of these variant CYP2C9 alleles have decreased clearance of S- Nicoumalone. In African patients, CYP2C9*2 and CYP2C9*3 occur at much lower allele frequencies 1-4% and 0.5-2.3%, respectively compared to Caucasians. Japanese population had lower allelic frequencies of 0.1% and 1-6% for CYP2C9*2 and CYP2C9*3, respectively]. The maintenance dose of nicoumalone differs based on the genotype. Detailed information of mean and median maintenance dose based on CYP2C9 genotype is given in the table below:

Table 1 CYP2C9 genotype and maintenance dose of Nicoumalone

Toxicity

After a single (acute) oral and/or intravenous dose, Nicoumalone showed a low degree of toxicity in mice, rats, and rabbits. In dogs, high acute oral toxicity was seen. In repeated-dose studies, the liver is suggested to be the main target organ in the toxicity of coumarin derivatives including Nicoumalone. The administration of these substances at excessive pharmacological doses can cause haemorrhages.

Reproduction toxicity, teratogenicity

No reproductive toxicity studies were performed with Nicoumalone. However, placental and transplacental interference with vitamin K dependent coagulation factors may give rise to embryonic or foetal anomalies and neonatal haemorrhages both in animals and in humans.

Mutagenicity

From investigations on bacterial and mammalian cell systems in vitro, including a DNA repair assay on rat hepatocytes, it can be concluded that Nicoumalone and/or its metabolites did not exert any mutagenic effects. An in vitro study on human lymphocytes has shown some mild mutagenic activity at a concentration of Nicoumalone, 500 to 1000 times higher than concentrations determined in human plasma after medication with Nicoumalone.

Carcinogenicity

No lifetime-exposure studies were carried out in animals with Nicoumalone. Coumarin, induced an increase in the incidence of lung and benign liver tumours in mice, and liver and benign kidney tumours in rats. Liver tumours in rats and lung tumours in mice are understood to be associated with species-specific metabolic pathways in these species. Hepatoxicity of coumarin and its derivatives in the rat is understood to be associated with enzyme induction and the metabolic pathway of coumarin and/or its metabolites peculiar to this rodent species. Renal tumours observed in male mice are considered to be a species-specific effect.

Nicoumalone is a 4-hydroxycoumarin derivative with anticoagulant activity. As a vitamin K antagonist, Nicoumalone inhibits vitamin K epoxide reductase, thereby inhibiting the reduction of vitamin K and the availability of vitamin KH2. This prevents gamma carboxylation of glutamic acid residues near the N-terminals of the vitamin K-dependent clotting factors, including factor II, VII, IX, and X and anticoagulant proteins C and S. This prevents their activity and thus thrombin formation. Compared to other coumarin derivatives, Nicoumalone has a short half-life.

Chemical Structure

IUPAC Name: 4-hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]chromen-2-one Molecular Formula: C₁₉H₁₅NO₆ Molecular Weight: 353.3 g/mol

Incompatibilities

None stated.

Shelf-life

24 months

Packaging information

10 blister strips of 10 tablets each

Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 300C. Keep out of reach of children.

• Nicoumalone can cause major (including hemorrhagic and hypovolemic shock) or fatal bleeding. Risk factors for bleeding include
  • high intensity of anticoagulation (INR >4.0)
  • age ≥ 65, history of highly variable INRs
  • history of gastrointestinal bleeding
  • hypertension, cerebrovascular disease
  • serious heart disease
  • anemia, malignancy, trauma
  • renal insufficiency, concomitant drugs
• Regular monitoring of INR should be performed on all treated patients.
• Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy.
• In paediatric and elderly patients (≥65 years), caution and more frequent monitoring of PT/INR is recommended

Ursodeoxycholic acid

Ursomax 150

Each uncoated tablet contains

Ursodeoxycholic acid IP.…………………………150 mg

Excipients……………………………………………...…...q.s.

Ursomax 300

Each uncoated tablet contains

Ursodeoxycholic acid IP.……………………………300 mg

Excipients……………………………………………...…...q.s.

Ursomax 450 SR

Each prolonged-release uncoated tablet contains

Ursodeoxycholic acid IP.……………………………450 mg

Excipients……………………………………………......q.s.

Tablet 150 mg/300 mg/450 mg

4.1 Therapeutic Indication

For the dissolution of radiolucent cholesterol gallstone, chronic cholestatic liver diseases in particular primary biliary cirrhosis, primary sclerosing cholangitis & cholestasis associated with cystic fibrosis.

4.2 Posology and method of administration

The dosage should be calculated based on the patient's body weight. The calculated dosage should be rounded to the nearest number of tablets.

Dissolving of cholesterol stones

Usual dosage: 8 to 10 mg/kg/day, corresponding to, for example, four to six 150 mg tablets, or two to three tablets of 300 mg, or two tablets of 450 mg. The daily dose can be administered two or three times after the meals: two tablets should always be taken after the evening meal.

Also a single evening dose can be selected (e.g., a patient of 60 kg, in the evening two tablets of 300 mg). Preferably, this single dose should be taken one hour before bedtime and ± two hours after the evening meal with a glass of milk or a small snack.

The duration of the treatment in order to obtain lysis of the gallstones depends on their size, but is usually not shorter than three to four months. To assess the result of the therapy properly, it is necessary to determine the size of the stones accurately at the start of the treatment and to check this further regularly, for example every six months, by means of a new contrast X-ray recording and/or sonographic recording.

In patients in whom, after six months of treatment with the indicated dosage, the stones are not reduced in size, it is recommended to determine the lithogenic index in the bile by means of a duodenum drainage. When the bile has an index of > 1.0, it is unlikely that a favourable result can be obtained, and it is better to consider a different form of treatment for the gallstones.

Treatment should be continued for three to four months after it is established by means of ultrasound check that the gallstones are completely dissolved. An interruption of the treatment for three to four weeks results in a return to over-saturation of the bile and prolongs the overall duration of the therapy. The interruption of the treatment after the dissolving of the gallstones can be followed by a recurrence.

Primary Biliary Cholangitis (Primary biliary cirrhosis)

The dosage of Ursodeoxycholic acid in primary biliary cholangitis (stages I-III), amounts to 12-15 mg/kg/day, which is equivalent to four to eight tablets of 150 mg, two to four tablets of 300 mg, to be taken in two to three portions during the day, or with two tablets of 450 mg, to be taken in two portions during the day.

The dosage of ursodeoxycholic acid in primary biliary cholangitis stage IV and an increase of the serum bilirubin contents (> 40 μg/l), should be in the first instance, only a half of the normal dose (6 to 8 mg/kg/day). Thereafter, the liver function should be closely monitored for several weeks (once every two weeks for six weeks). If there is no deterioration of the liver function (AF, ALT (SGPT), AST (SGOT), γ-GT, bilirubin) and no increase in itching occurs, the dose may be further increased to the usual level. Moreover, the liver function must then again be closely monitored for several weeks. If again no deterioration of the liver function takes place, the patient may be held at the normal dosage for a long time.

In patients with primary biliary cholangitis stage IV without elevated serum bilirubin, the usual starting dose is allowed to be administered directly. Anyway, here too an accurate control of the liver function should be executed.

The treatment of the primary biliary cholangitis should be regularly assessed on the basis of liver values (laboratory) and clinical findings.

Paediatric population

Children with cystic fibrosis aged 6 years to 18 years

Treatment of hepatobiliary diseases as a result of cystic fibrosis 20 mg/kg/day divided in two to three divided doses. If necessary, increase to 30 mg/kg/day. This corresponds with four to ten tablets of 150mg, two to five tablets of 300 mg, or with two to three tablets of 450 mg, to be taken in one or two portions during the day

Method of administration

If the patient has difficulty in swallowing because of the size of the tablet, the tablet can be halved if necessary on the dividing score, so that one half tablet can be taken twice directly in sequence.

4.3 Contraindications

Ursodeoxycholic acid tablets should not be used in patients with:

• Acute inflammation of the gall bladder or bile ducts
• Occlusion of the biliary tract (occlusion of the common bile duct or a cystic duct)
• Frequent episodes of biliary colic
• X-ray radiolucent calcified gallstones
• Impaired contractility of the gallbladder
• Hypersensitivity to bile acids or to any of the excipient
• Active gastric and duodenal ulcers

Paediatric population

• Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia.

4.4 Special warnings and precautions for use

Ursodeoxycholic acid tablets should be taken under medical supervision.

During the first three months of the treatment liver function parameters AST (SGOT), ALT (SGPT) and γ-GT should be monitored by the physician every 4 weeks, thereafter every 3 months. Apart from allowing for identification of responders and non-responders in patients being treated for primary biliary cholangitis, this monitoring would also enable an early detection of potential hepatic deterioration, particularly in patients with advanced primary biliary cholangitis.

When used for dissolving gallstones:

In order to be able to assess the therapeutic progression of the dissolution of gallstones and to timely identify a possible calcification of the stones, the gall bladder, depending on the size of the stones, should be visualized 6 to 10 months after the start of the treatment (oral cholecystography) with total image and occlusions and in the standing and lying position (ultrasound investigation).

If the gallbladder cannot be visualized on X-rays, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, the treatment with Ursodeoxycholic acid should be discontinued.

When used for the treatment of advanced primary biliary cholangitis:

In very rare cases decompensation of liver cirrhosis is observed which partially decreased after treatment discontinuation.

In patients with PBC, the clinical symptoms may worsen in rare cases at the start of treatment, e.g. pruritus may increase. In this case, the therapy is to be continued with a dose reduction and subsequently should be gradually increased to the recommended dose as described in section 4.2.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea.

Female patients who use Ursodeoxycholic acid for dissolving gall stones must use an effective non-hormonal method of contraception, since hormonal contraception may increase biliary lithiasis

4.5 Drugs interactions

• Ursodeoxycholic acid tablets should not be used concurrently with colestyramine, colestipol, or an antacid, on the basis of aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind ursodeoxycholic acid in the intestine and thereby inhibits its absorption and efficacy. If the use of such a medicine is necessary, must it be taken at least 2 hours before or after ursomax.
• Ursodeoxycholic acid may affect the absorption of ciclosporin from the intestine. In patients treated with ciclosporin the blood level of ciclosporin should be monitored and the ciclosporin dose should be adjusted, if necessary.
• In isolated cases Ursodeoxycholic acid can reduce the absorption of ciprofloxacin.
• In a clinical study in healthy volunteers, the concomitant use of UDCA (500 mg/day) and rosuvastatin (20 mg/day) resulted in slightly elevated plasma levels of rosuvastatin.The clinical relevance of this interaction, also with other statins, is not known.
• Ursodeoxycholic acid has been shown to reduce the peak plasma concentration (Cmax) and the AUC of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and ursodeoxycholic acid is recommended. An increase of the dose of nitrendipine may be necessary. An interaction with a reduction of the therapeutic effect of dapsone was also reported. These observations, together with in vitro findings could be an indication that ursodeoxycholic acid can induce cytochrome P450 3A enzymes. Induction has, however not been observed in a well-designed interaction study with budesonide, which is a known cytochrome P450 3A substrate.
• Oestrogens and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and may therefore encourage biliary lithiasis; which is a counter-effect to ursodeoxycholic acid used for dissolution of gallstones.

4.6 Use in special populations

Pregnancy

• There are no or limited amount of data from the use of ursodeoxycholic acid in pregnant women. Studies in animals have shown reproductive toxicity during the early gestation phase.
• Ursodeoxycholic acid must not be used during pregnancy, unless clearly necessary.

Women of childbearing potentialc

• Women of childbearing potential should be treated with ursodeoxycholic acid, only if they practice reliable contraception: non-hormonal contraceptives or oral contraceptives with low oestrogen dose are recommended. However, in patients taking Ursodeoxycholic acid for dissolving gallstones an effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis.
• The possibility of a pregnancy must be excluded before beginning treatment.

Nursing Mothers

• According to few documented cases of breastfeeding women milk levels of ursodeoxycholic acid levels in milk are very low and probably no adverse reactions are to be expected in breastfed infants.

Fertility

Animal studies did not show an influence of ursodeoxycholic acid on fertility. Human data on fertility treatment with ursodeoxycholic acid are not available.

4.7 Effects on ability to drive and use machines

Ursodeoxycholic acid has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency:

very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Gastrointestinal disorders:

In clinical studies, reports of pasty stools or diarrhoea during treatment with ursodeoxycholic acid were common.

In very rare cases, severe right upper abdominal pain has occurred during the treatment of primary biliary cholangitis.

Hepatobiliary disorders:

During treatment with ursodeoxycholic acid calcification of gallstones can occur in very rare cases.

During the treatment of advanced stages of primary biliary cholangitis decompensation of cirrhosis has been observed in very rare cases, which partially regressed after treatment discontinuation.

Hypersensitivity reactions:

Very rarely urticaria may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting &nbsp;

4.9 Overdose

In the case of overdose diarrhoea may occur. In general, other symptoms of overdose are unlikely, because the absorption of the ursodeoxycholic acid decreases with increasing dose and therefore more is excreted in the faeces.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea. No specific measures are needed and the consequences of diarrhoea should be treated symptomatically with restoration of fluid and electrolyte balance.

Additional information or special populations: Long-term, high-dose UDCA therapy (28-30 mg/kg/day) by patients with primary sclerosing cholangitis (off-label use) was associated with a higher frequency of serious adverse events.

5.1 Mechanism of Action

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

5.2 Pharmacodynamic properties

Bile acids are among the most important components of the bile and play a role in the stimulation of bile secretion. Bile acids are also important to keep the cholesterol in bile in solution. In a healthy person, the ratio between the concentration of cholesterol and bile acids in the bile is such that the cholesterol will remain in solution for most of the day. In this case, no gallstones can form (the bile is non-lithogenic). In patients with cholesterol stones in the bile, this ratio is changed and the bile is supersaturated with cholesterol (bile is lithogenic). This may cause a precipitation of cholesterol crystals and the formation of gallstones after some time.

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

Investigations of the effect of ursodeoxycholic acid on the cholestasis in patients with impaired biliary drainage and on the clinical symptoms in patients with primary biliary cholangitis and cystic fibrosis have shown that cholestatic symptoms in the blood (to be measured by the increased value of alkaline phosphatase (AF), gamma-GT and bilirubin) and the itch declined rapidly, while also the fatigue decreased in the majority of patients. Moreover, studies seem to indicate a positive benefit-risk ratio of the ursodeoxycholic acid in children and young adult cystic fibrosis patients with mild to moderate hepatobiliary disorders.

Paediatric population

Cystic fibrosis

From clinical reports long-term experience of 10 years and more has been gained with UDCA therapy in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can inhibit bile duct proliferation, can halt progression of histological damage and even reverse hepato-biliary changes, if it happens at an early stage of CFAHD. The treatment with UDCA should be started as soon as the CFAHD diagnosis is made, in order to optimize the effectiveness of the treatment.

5.3 Pharmacokinetic properties

About 90% of the therapeutic dose of the ursodeoxycholic acid is rapidly absorbed in the small intestine after oral administration.

After the absorption, ursodeoxycholic acid is absorbed in the liver (there is a substantial "first-passeffect"), where it is conjugated with glycine or taurine and then secreted into the bile ducts. Only a small portion of ursodeoxycholic acid is found in the systemic circulation. This is excreted renally. With the exception of conjugation, ursodeoxycholic acid is not metabolised. However, a small fraction of orally administered ursodeoxycholic acid undergoes bacterial conversion to 7-keto-lithocholic acid resp. lithocholic acid after each enterohepatic circulation, while bacterial deconjugation also takes place in the duodenum. Ursodeoxycholic acid, 7-keto-lithocholic acid and lithocholic acid are relatively poorly soluble in water, so a large part of it is excreted via the bile into the faeces. Resorbed ursodeoxycholic acid is conjugated again by the liver; 80% of the lithocholic acid formed in the duodenum is excreted in the faeces, but the remaining 20% of it are sulphated by the liver to insoluble lithocholylconjugates after absorption, which in turn are excreted via the bile and faeces. Resorbed 7- keto-lithocholic acid is reduced to chenodeoxycholic acid in the liver. Lithocholic acid can cause cholestatic liver damage, when the liver is unable to sulphate the lithocholic acid. Although a reduced capacity to sulphate the lithocholic acid in the liver is found in some patients, there is for the time being no clinical evidence that cholestatic liver damage can be associated with the therapy using ursodeoxycholic acid.

After repeated dosage, the ursodeoxycholic acid concentration in the bile reaches a "steady state" after approximately 3 weeks: the total concentration of the ursodeoxycholic acid, however, is never higher than about 60% of the total concentration of the bile acid in the bile: also at high doses.

After therapy with ursodeoxycholic acid is stopped, the concentration of ursodeoxycholic acid in bile decreases quickly after 1 week to 5-10% of the "steady-state" concentration.

The biological half-life of ursodeoxycholic acid is approximately 3.5 to 5.8 days.

6.1 Animal Toxicology or Pharmacology

Acute toxicity

Acute toxicity studies in animals have not revealed any toxic damage.

b) Chronic toxicity

Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of ursodeoxycholic acid, which in monkeys – unlike humans – is not detoxified. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.

c) Carcinogenic and mutagenic potential

Long-term studies in mice and rats revealed no evidence of ursodeoxycholic acid having carcinogenic potential. In vitro and in vivo genetic toxicology tests with ursodeoxycholic acid were negative. The tests with ursodeoxycholic acid revealed no relevant evidence of a mutagenic effect.

d) Toxicity to reproduction

In studies in rats, tail malformations occurred after a dose of 2000 mg per kg of body weight. In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). ursodeoxycholic acid had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. The chemical name of ursodiol is 3α,7ß-dihydroxy-5ß-cholan-24-oic (C₂₄H₄₀O₄)

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 Blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store in a cool, dry & dark place.
• Keep out of reach of children.
• Tablet should be swallowed whole & not to be broken, chewed or crushed.

• Ursomax tablet should be taken after a meal with a glass of milk or water.
• Eat a healthy diet, exercise regularly, and avoid alcohol intake.
• Diarrhea may occur as a side effect. Drink plenty of fluids and inform your doctor if diarrhea persists or if you find blood in your stools.
• Your doctor may monitor your liver function and bilirubin levels every month for the next 3 months after the start of therapy, and every 6 months thereafter.
• Do not stop taking the medication without talking to your doctor.

28.08.2024

Lactitol Monohydrate Syrup 66.67% w/v

Each 15 ml syrup contains:

Lactitol Monohydrate USP 10 g

Benzoic Acid USP 0.0225 g

Syrup

10 g/15ml in 100/200 ml bottles

4.1 Therapeutic indications

Gutclear® Syrup is indicated for treatment of chronic constipation and prevention of hepatic encephalopathy.

4.2 Posology and method of administration

In the treatment of constipation, the recommended dose of Gutclear® Syrup is as follows

Adults:

The recommended adult dosage of Gutclear® Syrup is 30 ml (20 grams) orally once daily, preferably with meals.

Reduce the dosage to 15 ml (10 grams) once daily for persistent loose stools.

Pediatrics: 250-400 mg/kg/day

Gutclear® Syrup is given as a single dose with the morning or evening meal, subsequently adjusted to produce one stool daily.

In the treatment of hepatic encephalopathy, Gutclear® Syrup is given in usual oral doses of 500 to 700 mg/kg daily in 3 divided doses at meal times. The dose is subsequently adjusted to produce 2 soft stools daily.

Administration Instructions

Doses should be mixed with food or liquid, and it is recommended to drink 1 to 2 glasses of liquid with the meal.

Administer other oral medications at least 2 hours before or 2 hours after Gutclear® Syrup.

4.3 Contraindications

Gutclear® Syrup is contraindicated in:

• Patients with the undiagnosed abdominal pain, colic, bleeding or vomiting
• Patients with intestinal obstruction, ileostomy, colostomy, appendicitis or diverticulitis
• Patients with galactosemia
• Patients hypersensitive to the drug or any other component of the formulation

4.4 Special warnings and precautions for use

• It is suggested that individuals taking Gutclear® Syrup have their fluid and salt (electrolyte) balance monitored regularly especially in elderly patients on long term treatment.
• Treatment with Gutclear® Syrup may cause accumulation of hydrogen in the bowel; patient should be advised to have a thorough bowel cleansing with a non-fermentable solution.

4.5 Interaction with other medicinal products and other forms of interaction

Reduced Absorption of Other Oral Medications Gutclear® Syrup may reduce the absorption of concomitantly administered oral medications. Administer oral medications at least 2 hours before or 2 hours after Gutclear® Syrup [see Dosage and Administration] Gutclear® Syrup should not be administered with other laxatives.

Caution may be exercised in using Gutclear® Syrup with drugs causing potassium loss like loop diuretics.

Gutclear® Syrup can increase digitalis toxicity.

Reduction in acidification effect can be observed if broad spectrum antibacterial agents or antacids are administered along with Gutclear® Syrup.

4.6 Pregnancy and lactation

Pregnancy

Lactitol is minimally absorbed systemically following oral administration, and it is unknown whether maternal use will result in fetal exposure to the drug. Available data from case reports on lactitol use in pregnant women are insufficient to evaluate for any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of lactitol to rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Gutclear® Syrup should be prescribed only if the potential benefits outweigh the risks to the fetus.

Animal Data

Reproduction studies have been performed in pregnant rats at oral doses of lactitol up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area) and in pregnant rabbits at oral doses up to 1 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area) administered during the period of organogenesis. These studies did not reveal any evidence of harm to the fetus due to lactitol.

In a pre-and postnatal development study in rats, lactitol, administered from gestation day 6 to lactation day 20, did not cause any adverse effect on pre and postnatal development up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area).

Lactation

There are no data on the presence of lactitol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Lactitol is minimally absorbed systemically following oral administration. It is unknown whether the minimal systemic absorption of lactitol by adults will result in a clinically relevant exposure to breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Gutclear® Syrup and any potential adverse effects on the breastfed infant from Gutclear® Syrup or from the underlying maternal condition.

No studies are available on the secretion of lactitol in breast milk.

4.7 Effects on ability to drive and use machines

Lactulose has no or negligible influence on your ability to drive safely or use machines.

Undesirable effects

The most commonly observed adverse effects with Gutclear® Syrup are abdominal cramps, distensionor flatulence during the first 10 days of treatment which are likely to disappear after continued administration. The other less frequent side effects are abdominal pain, diarrhoea, nausea and vomiting, anal pruritus, borborygmii or steatorrhea.

Reporting of suspected adverse reactions

• Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com
• Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.8 Overdose

No data on overdosage of Lactitol is available. If a patient consumes large amount of Lactitol, symptoms of abdominal pain and diarrhea may appear. There may also be electrolyte imbalance. There is no specific antidote known for Lactitol over dosage. Gastric lavage may be instituted at the earliest to remove the remnant drug from the stomach. Patient should be treated symptomatically and electrolyte levels should be monitored periodically.

5.1 Pharmacodynamic properties

Mechanism of action

Once ingested, Lactitol is neither hydrolysed nor absorbed in the small intestine. It is passed undigested to the colon and a substantial proportion of orally ingested lactitol becomes substrate for the resident colonic microflora where it is slowly fermented and is converted into short-chain fatty acids (SCFAs). The liberation of short-chain fatty acids causes a fall in pH of the right colon. The fall in pH results in the formation of an acidic media.

The reduction in intra-luminal pH increases the intra-luminal osmolality. This promotes retention of water within the bowel lumen, softening the stool and increasing the bowel volume. Hydration of the gut content and reduction in intra-luminal pH also results in shorter transit time and the establishment of laxation.

Lactitol decreases blood ammonia concentration by inhibiting both the production and the absorption of ammonia by reducing intestinal pH and shortening the residence time of intestinal contents in the intestinal tract and hence improves hepatic encephalopathy. Lactitol also favors the growth of saccharolytic (healthy) bacteria in the gut.

5.2 Pharmacokinetic Properties

Following a single oral dose of 20-gram Lactitol in healthy adult subjects under fed conditions, the mean ± SD peak serum concentration (Cmax) is 776 ± 253 ng/mL, and the mean ± SD area under the curve (AUC) is 6,019 ± 1,771 ng*hr/mL.

Absorption

Lactitol is minimally absorbed systemically following oral administration. The mean ± SD time to reach peak serum concentration (Tmax) is 3.6 ± 1.2 hours following a single oral dose of 20-gram Lactitol in healthy adult subjects under fed conditions.

Effect of Food

Cmax and AUC values increase greater than 2-fold under fasted conditions compared to fed conditions.

Elimination

The mean half-life of lactitol is 2.4 hours.

Excretion

6.1 Preclinical safety data

A perinatal and postnatal study of lactitol, a hepatic encephalopathy drug was conducted in Sprague-Dawley rats. Female rats were given lactitol orally at dose levels of 0 (control), 0.7, 2.65 and 10 g/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats per level were allowed to deliver naturally for postnatal examination of their offspring. The high dose caused diarrhea or soft stool in dams. The high dose suppressed the body weight of dams during the perinatal period. The food consumption of dams decreased in the intermediate and high dose groups. The water consumption of dams increased in the high dose group. The high dose caused enlargement of cecum and increase of weights of cecum in dams. The drug failed to affect the delivery of dams and gestation index. However, high dose caused prolongation of gestation period. Two dams in the high dose group failed to nurse their all newborns during early lactation. The drug did not affect the number of live newborns, birth index, external appearance, body weight, viability index, weaning index, and sex ratio of weanlings. Nor did lactitol have any adverse effect on the postnatal development of the first (F1) generation offspring, such as differentiation, emotionality, motor ability, learning ability or reproductive performance. Nor did lactitol have any adverse effect on the second (F2) generation offspring. The results show that the no-effect dose levels of lactitol are 0.7 g/kg for general toxicity in mother animals, 2.65 g/kg for reproductive function in mother animals, and 10 g/kg for their offspring.

Lactitol is an osmotic laxative for oral use. Lactitol is a simple monosaccharide sugar alcohol. It is a dry, free flowing, white to off-white powder, readily soluble in aqueous solutions. As shown by the structure diagrams, it is an analog of the disaccharide lactulose. Its chemical name is 4-O-β-dGalactopyranosyl-d-glucitol lactitol.

Molecular Formula C₁₂H₂₄O₁₁

Molecular Weight 344.31

Gutclear® Syrup ® (lactitol) for oral solution is available in multi-dose bottles.

8.1 List of excipients

Benzoic Acid and Purified water

8.2 Incompatibilities

Gutclear® Syrup may reduce the absorption of concomitantly administered oral medications. Administer oral medications at least 2 hours before or 2 hours after Gutclear® Syrup

8.3 Shelf life

36 months

8.4 Special precautions for storage

Store below 30°C. Protect from light. Do not freeze

8.5 Nature and contents of container

100 ml or 200 ml filled in amber colour pet bottle of 200 ml with a silver pp cap with ep wad and 15 ml measuring cup. One such pack is placed along with a leaflet in a carton.

8.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Persistent Loose Stools Advise patients to stop Gutclear® Syrup ® Syrup and contact their healthcare provider if they experience persistent loose stools.

Dydrogesterone Tablets IP 10 mg

Each film coated tablet contains :

Dydrogesterone IP 10 mg

Colour : Titanium Dioxide IP

Tablet 10 mg

4.1 Therapeutic indication

Progesterone deficiencies

• Treatment of dysmenorrhoea
• Treatment of endometriosis.
• Treatment of secondary amenorrhoea.
• Treatment of irregular cycles.
• Treatment of dysfunctional uterine bleeding.
• Treatment of pre-menstrual syndrome.
• Treatment of threatened abortion.
• Treatment of habitual abortion.
• Treatment of infertility due to luteal insufficiency.
• Luteal Support as a part of Assisted Reproductive Technology (ART) treatment.

Hormone replacement therapy

To counteract the effects of unopposed oestrogen on the endometrium in hormone replacement therapy for women with disorders due to natural or surgical induced menopause with an intact uterus.

4.2 Posology and method of administration

Dosages, treatment schedule and duration of treatment may be adapted to the severity of the dysfunction and the clinical response.

Dysmenorrhoea : 10 or 20 mg Dydrogesterone per day from day 5 to day 25 of the Menstrual cycle.

Dysfunctional uterine bleeding : When treatment is started to arrest a bleeding episode, 20 or 30 mg Dydrogesterone per day is to be given for up to 10 days. For continuous treatment, 10 or 20 mg Dydrogesterone per day should be given during the second half of the menstrual cycle. The starting day and the number of treatment days will depend on the individual cycle length.

Withdrawal bleeding occurs if the endometrium has been adequately primed with either endogenous or exogenous estrogen.

Secondary amenorrhoea : 10 or 20 mg Dydrogesterone per day, to be given daily for 14 days during the second half of the theoretical menstrual cycle to produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen.

Pre-menstrual syndrome : 10 mg Dydrogesterone twice daily starting with the secondhalf of the menstrual cycle until the first day of the next cycle. The starting day and the number of treatment days will depend on the individual cycle length.

Irregular cycles : 10 or 20 mg Dydrogesterone per day starting with the second half of the menstrual cycle until the first day of the next cycle. The starting day and the number of treatment days will depend on the individual cycle length.

Threatened abortion : An initial dose of up to 40 mg Dydrogesterone may be given followed by 20 or 30 mg per day until symptoms remit

Habitual abortion : 10 mg Dydrogesterone twice daily until the twentieth week of pregnancy.

Infertility due to luteal insufficiency : 10 or 20 mg Dydrogesterone daily starting with the second half of the menstrual cycle until the first day of the next cycle. Treatment should be maintained for at least three consecutive cycles.

Hormone replacement therapy :

• Continuous sequential therapy : An estrogen is dosed continuously and one tablet of 10 mg Dydrogesterone is added for the last 14 days of every 28 day cycle, in a sequential manner.
• Cyclic therapy : When an estrogen is dosed cyclically with a treatment-free interval, usually 21 days on and 7 days off. One tablet of 10 mg Dydrogesterone is added for the last 12 -14 days of estrogen therapy.
• Depending on the clinical response, the dosage can subsequently be adjusted to 20 mg Dydrogesterone per day.

There is no relevant use of Dydrogesterone before menarche. The safety and efficacy of Dydrogesterone in adolescents aged 12-18 years has not been established. Currently available data are described in 'Adverse Reactions and 'Pharmacodynamic Properties', but no recommendation on a posology can be made.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Known or suspected progestogen dependent neoplasms (e.g. meningioma)
• Undiagnosed vaginal bleeding.
• If used to prevent endometrial hyperplasia (in women using estrogens) : Contraindications for use of oestrogens in combination with progestagens, such as Dydrogesterone.

4.4 Special warnings and precautions for use

Before initiating Dydrogesterone treatment for abnormal bleeding the etiology for the bleeding should be clarified. Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Dydrogesterone and ceasing the treatment should be considered :

Porphyria

Depression

Abnormal liver function values caused by acute or chronic liver disease

Other conditions

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.

The following warnings and precautions apply when using Dydrogesterone in combination with estrogens for hormone replacement therapy (HRT) :

See also the warnings and precautions in the product information of the estrogen preparation.

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk. Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination / follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including appropriate imaging tools, e.g., mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Endometrial hyperplasia

Long-term use of oestrogens without addition of progestagens increases the change of endometrial hyperplasia and endometrial carcinoma in women with a uterus. This risk may largely be prevented by combining the oestrogen therapy for at least 12 days per cycle with a progestagen, such as Dydrogesterone.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT. The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies including the WHI trial suggest that use of combined HRTs may be associated a similar, or slightly smaller, risk.

Venous thrombo-embolism

HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later. Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients. Generally recognized risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilization is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilized. In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated. Women already on chronic anticoagulant treatment require careful consideration of the benefit risk of use of HRT. If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogenprogestogen or estrogen-only HRT

Combined estrogen-progestogen therapy

The relative risk of CAD during use of combined estrogen progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen-progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Cerebrovascular accident (CVA)

Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly agedependent, the overall risk of stroke in women who use HRT will increase with age.

4.5 Drugs interactions

In vitro data show that the major metabolic pathway generating the main pharmacologically active metabolite 20α Dihydrodydrogesterone (DHD) is catalyzed by aldo-keto reductase 1C (AKR 1C) in human cytosol. Next to the cytosolic metabolism there are metabolic transformations by cytochrome P450 iso-enzymes (CYPs), nearly exclusively via CYP3A4, resulting in several minor metabolites. The main active metabolite DHD is substrate for metabolic transformation by CYP3A4. Therefore, the metabolism of Dydrogesterone and DHD may be increased by concomitant use of substances known to induce CYP enzymes such as anticonvulsants (e.g., Phenobarbital, Phenytoin, Carbamazepine), anti-infectives (e.g., Rifampicin, Rifabutin, Nevirapine, Efavirenz) and herbal preparations containing e.g. St John's Wort (Hypericumperforatum), sage, or gingko biloba. Ritonavir and nelfinavir, although known as strong cytochrome enzyme inhibitors, by contrast exhibit enzyme-inducing properties when used concomitantly with steroid hormones. Clinically, an increased metabolism of Dydrogesterone may lead to a decreased effect. In vitro studies have shown that Dydrogesterone and DHD do not inhibit or induce CYP drug metabolizing enzymes at clinically relevant concentrations.

4.6 Use in special populations

Pregnancy

It is estimated that more than 9 million pregnancies have been exposed to Dydrogesterone. So far there were no indications of a harmful effect of Dydrogesterone use during pregnancy. Some progestogens have been reported in the literature to be associated with an increased risk of hypospadias. However due to confounding factors during pregnancy, no definitive conclusion can be drawn regarding the contribution of progestogens to hypospadias. Clinical studies, where a limited number of women were treated with Dydrogesterone early in pregnancy, have not shown any increase in risk. No other epidemiological data are hitherto available. Effects in non-clinical embryo-fetal and post-natal development studies were in line with the pharmacological profile. Untoward effects occurred only at exposures which exceeded the maximum human exposure considerably, indicating little relevance to clinical use. Dydrogesterone can be used during pregnancy if clearly indicated.

Breast feeding

No data exist on excretion of Dydrogesterone in mother's milk. Experience with other progestogens indicates that progestogens and the metabolites pass to mother's milk in small quantities. Whether there is a risk to the child is not known. Therefore, Dydrogesterone should not be used during the lactation period.

Fertility

There is no evidence that Dydrogesterone decreases fertility at therapeutic dose.

4.7 Effects on ability to drive and use machines

Dydrogesterone has a slight effect on ability to drive and to use machinery. In rare cases Dydrogesterone may cause somnolence and/or dizziness, in particular during the first couple of hours after taking it. Caution is therefore advised when driving and operating machinery.

4.8 Undesirable effects

* Adverse effects reported spontaneously

Undesirable effects that are associated with an estrogen-progestogen treatment (see also 'Warnings and Precautions' and the product information of the estrogen preparation) :

Breast cancer, Endometrial hyperplasia, Endometrial carcinoma, Ovarian cancer

Venous thromboembolism

Myocardial infarction, Coronary artery disease, Ischemic stroke

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via e-mail to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms

Dydrogesterone is a substance with very low toxicity. Nausea, vomiting, lethargy and dizziness are symptoms which may theoretically occur in the event of an overdose. There are no known cases in which an overdose of Dydrogesterone led to harmful effects.

Treatment

Specific treatment is clearly not necessary. In case of overdose symptomatic treatment may be considered.

5.1 Mechanism of action

Dydrogesterone is an orally-active progestogen which produces a complete secretory endometrium in an estrogen-primed uterus thereby providing protection against the increased risk for endometrium hyperplasia and/or carcinogenesis induced by estrogens. It is indicated in all cases of endogenous progesterone deficiency.

5.2 Pharmacodynamic properties

Dydrogesterone has no estrogenic, no androgenic, no thermogenic, no anabolic and no corticoid activity. Dydrogesterone does not suppress ovulation.

5.3 Pharmacokinetic properties

Absorption

After oral administration Dydrogesterone is rapidly absorbed with a Tmax of between 0.5 and 2.5 hours. The absolute biological availability of Dydrogesterone (20 mg oral dose versus 7.8 mg intravenous infusion) is 28%. The following tables gives the pharmacokinetic parameters of Dydrogesterone (D) and 20α Dihydrodydrogesterone (DHD) after administration of a single dose of 10 mg Dydrogesterone :

Distribution

After intravenous administration of Dydrogesterone the steady-state distribution volume is around 1400 l. More than 90% of Dydrogesterone and DHD are bound to plasma-proteins.

Metabolism

After oral administration Dydrogesterone is quickly metabolised to DHD. The plasma levels of the main active metabolite DHD show a peak around 1.5 hours after administering the dose. The plasma levels of DHD are substantially higher than the related medicinal product. The AUC and Cmax ratios of DHD and Dydrogesterone are of the order of magnitude of respectively 40 and 25. The mean terminal half-life of Dydrogesterone and DHD varies from respectively 5 to 7 and 14 to 17 hours. A common characteristic of all characterised metabolites is the retention of the 4,6-diene-2-one configuration of the original product and the absence of 17α hydroxylation. This explains the absence of oestrogenic and androgenic effects of Dydrogesterone.

Elimination

After oral administration of labelled Dydrogesterone on average 63% of the dose is excreted in the urine. The total plasma clearance is 6.4 l/minute. Within 72 hours the excretion is complete, DHD is present in the urine mainly as the conjugated glucuronic acid.

6.1 Animal toxicology or pharmacology

Non-clinical data obtained during conventional investigation into the toxixcity of single and repeated doses, genotoxicity and the carcinogenic potential do not show any special risks for humans. Research into the toxic effects on the reproduction of rats shows for high doses (> 80 times the human exposure) an increased incidence of erect nipples (during days 11-19 of the lactation period) and of hypospadia in male rats. The clinical relevance of these observations is not known. The limited data on safety in animals indicate that Dydrogesterone has an extending effect on delivery, which corresponds with the progestogenic action.

Dydrogesterone is a synthetic progesterone with an oral biological availability that causes a secretory phase of the endometrium in a uterus prepared by oestrogen. It gives protection against the increased risk of endometrial hyperplasia and/or endometrial carcinoma that is induced by oestrogens.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

PVC/PVDC-Alu blister pack of 10 tablets.

8.4 Storage and handing instructions

Store at temperature not exceeding 25°C. Protect from light

Keep out of reach of children.

Ask the patient to report any adverse events.

Ask the patients if Porphyria, Depression, Abnormal liver function values caused by acute or chronic liver disease is present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment.

Patients should be asked to exercise caution when driving and operating machinery

Ask the patient to report if breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued.

31 May 2022

Sacubitril and Valsartan Tablets 50 mg / 100 mg / 200 mg

Zuvatan 50

Each film coated tablet contains :

24 mg Sacubitril and 26 mg Valsartan as sodium salt

Excipients q.s.

Colours : Iron Oxide Black, Iron Oxide Red and Titanium Dioxide IP

Zuvatan 100

Each film coated tablet contains :

49 mg Sacubitril and 51 mg Valsartan as sodium salt

Excipients q.s

Colours : Iron Oxide Yellow, Iron Oxide Red and Titanium Dioxide IP

Zuvatan 200

Each film coated tablet contains :

97 mg Sacubitril and 103 mg Valsartan as sodium salt

Excipients q.s.

Colours : Iron Oxide Black, Iron Oxide Red and Titanium Dioxide IP

Tablet, 50 (24 + 26) mg, 100 (49 + 51) mg, 200 (97 + 103) mg

4.1 Therapeutic indication

To reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

4.2 Posology and method of administration

General considerations

Zuvatan is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to Zuvatan allow a washout period of 36 hours between administration of the two drugs

Adult heart failure

The recommended starting dose of Zuvatan is 100 mg orally twice-daily. Double the dose of Zuvatan after 2 to 4 weeks to the target maintenance dose of 200 mg twice daily, as tolerated by the patient.

Dose adjustment for patients not taking an ace inhibitor or arb or previously taking low doses of these agents

In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start Zuvatan at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults and every 2 weeks in paediatric patients to follow the recommended dose escalation thereafter.

Dose adjustment for severe renal impairment

In adults and paediatric patients with severe renal impairment (eGFR < 30 mL/min/1.73 m ), start Zuvatan at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter.

No starting dose adjustment is needed for mild or moderate renal impairment.

Dose adjustment for hepatic impairment

In adults and paediatric patients with moderate hepatic impairment (Child-Pugh B classication), start Zuvatan at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter.

No starting dose adjustment is needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

Method of administration

Oral use

Zuvatan may be administered with or without food. The tablets must be swallowed with a glass of water.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in the formulation.
• Concomitant use with ACE inhibitors. Zuvatan must not be administered until 36 hours after discontinuing ACE inhibitor therapy.
• Known history of angioedema related to previous ACE inhibitor or ARB therapy.
• Hereditary or idiopathic angioedema.
• Concomitant use with Aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with  renal impairment (eGFR <60 ml/min/1.73 m² ).
• Severe hepatic impairment, biliary cirrhosis and cholestasis.
• Second and third trimesters of pregnancy.

4.4 Warning and precautions

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

The combination of Sacubitril / Valsartan with an ACE inhibitor is contraindicated due to the increased risk of angioedema. Sacubitril / Valsartan must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Sacubitril / Valsartan is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Sacubitril / Valsartan. The combination of Sacubitril / Valsartan with direct renin inhibitors such as Aliskiren is not recommended. The combination of Sacubitril / Valsartan with Aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or 2 in patients with renal impairment (eGFR <60 ml/min/1.73 m ). Zuvatan contains valsartan, and therefore should not be co-administered with another ARB containing medicinal product.

Hypotension

Treatment should not be initiated unless SBP is ≥ 100 mmHg. Patients with SBP < 100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with Sacubitril / Valsartan during clinical studies, especially in patients ≥ 65 years old, patients with renal disease and patients with low SBP (< 112 mmHg). When initiating therapy or during dose titration with Sacubitril / Valsartan, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of Sacubitril / Valsartan is recommended. Dose adjustment of diuretics, concomitant antihypertensive and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with Sacubitril / Valsartan, however, such corrective action must be carefully weighed against the risk of volume overload.

Impaired renal function

Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension). There is very limited clinical experience 2 in patients with severe renal impairment (estimated GFR < 30 ml/min/1.73 m ) and these patients may be at greatest risk of hypotension. There is no experience in patients with end-stage renal disease and use of Sacubitril / Valsartan is not recommended.

Worsening renal function

Use of Sacubitril / Valsartan may be associated with decreased renal function. The risk may be further increased by dehydration or concomitant use of non-steroidal anti-inammatory agents (NSAIDs). Down-titration should be considered in patients who develop a clinically signicant decrease in renal function.

Hyperkalaemia

Treatment should not be initiated if the serum Potassium level is > 5.4 mmol/l. Use of Sacubitril / Valsartan may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur. Monitoring of serum Potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high Potassium diet or on mineralocorticoid antagonists. If patients experience clinically signicant hyperkalaemia adjustment of concomitant medicinal products, or temporary down–titration or discontinuation is recommended. If serum Potassium level is > 5.4 mmol/l discontinuation should be considered.

Angioedema

Angioedema has been reported in patients treated with Sacubitril / Valsartan. If angioedema occurs, Sacubitril / Valsartan should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. It must not be re-administered. In cases of confirmed angioedema where swelling has been conned to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, e.g. Adrenaline solution 1 mg / 1 ml (0.3 - 0.5 ml), and/or measures necessary to ensure a patent airway, should be promptly administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Sacubitril / Valsartan is used in these patients. Sacubitril / Valsartan is contraindicated in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy or with hereditary or idiopathic angioedema. Black patients have an increased susceptibility to develop angioedema.

Patients with renal artery stenosis

Sacubitril / Valsartan may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended.

Patients with NYHA functional classification IV

Caution should be exercised when initiating Sacubitril / Valsartan in patients with NYHA functional classication IV due to limited clinical experience in this population.

B-type natriuretic peptide (BNP)

BNP is not a suitable biomarker of heart failure in patients treated with Sacubitril / Valsartan because it is a Neprilysin substrate.

Patients with hepatic impairment

There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classication) or with AST/ALT values more than twice the upper limit of the normal range. In these patients, exposure may be increased and safety is not established. Caution is therefore recommended when using it in these patients. Sacubitril / Valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification).

Psychiatric disorders

Psychiatric events such as hallucinations, paranoia and sleep disorders, in context of psychotic events, have been associated with Sacubitril / Valsartan use. If a patient experiences such events, discontinuation of Sacubitril / Valsartan treatment should be considered

4.5 Drug interactions

Interactions resulting in a contraindication

ACE inhibitors

The concomitant use of Sacubitril / Valsartan with ACE inhibitors is contraindicated, as the concomitant inhibition of Neprilysin (NEP) and ACE may increase the risk of angioedema. Sacubitril / Valsartan must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Sacubitril / Valsartan.

Aliskiren

The concomitant use of Sacubitril / Valsartan with Aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or 2 in patients with renal impairment (eGFR < 60 ml/min/1.73 m ). The combination of Sacubitril / Valsartan with direct renin inhibitors such as Aliskiren is not recommended. Combination of Sacubitril / Valsartan with Aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure).

Interactions resulting in concomitant use not being recommended

Sacubitril / Valsartan contains valsartan, and therefore should not be co-administered with another ARB containing medicinal product.

Interactions requiring precautions

OATP1B1 and OATP1B3 substrates, e.g. statins In vitro data indicate that Sacubitril inhibits OATP1B1 and OATP1B3 transporters. Zuvatan may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of Sacubitril / Valsartan increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised when co-administering Sacubitril / Valsartan with statins. No clinically relevant interaction was observed when simvastatin and Zuvatan were co-administered.

PDE5 inhibitors including Sildenafil

Addition of a single dose of Sildenafil to Sacubitril / Valsartan at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of Sacubitril / Valsartan alone. Therefore, caution should be exercised when Sildenafil or another PDE5 inhibitor is initiated in patients treated with Sacubitril / Valsartan.

Potassium

Concomitant use of Potassium-sparing diuretics (Triamterene, Amiloride), mineralocorticoid antagonists (e.g. Spironolactone, Eplerenone), Potassium supplements, salt substitutes containing Potassium or other agents (such as Heparin) may lead to increases in serum Potassium, and to increases in serum creatinine. Monitoring of serum Potassium is recommended if Sacubitril / Valsartan is co-administered with these agents.

Non-steroidal anti-inflammator y agents (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors

In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of Sacubitril / Valsartan and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying treatment in patients on Sacubitril / Valsartan who are taking NSAIDs concomitantly.

Lithium

Reversible increases in serum Lithium concentrations and toxicity have been reported during concomitant administration of Lithium with ACE inhibitors or angiotensin II receptor antagonists including Sacubitril / Valsartan. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum Lithium levels is recommended. If a diuretic is also used, the risk of Lithium toxicity may be increased further.

Furosemide

Co-administration of Sacubitril / Valsartan and Furosemide had no effect on the pharmacokinetics of Sacubitril / Valsartan but reduced Cmax and AUC of Furosemide by 50% and 28%, respectively. While there was no relevant change in urine volume, the urinary excretion of sodium was reduced within 4 hours and 24 hours after coadministration. The average daily dose of Furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with Sacubitril / Valsartan.

Nitrates, e.g. Nitroglycerine

There was no drug-drug interaction between Sacubitril / Valsartan and intravenously administered Nitroglycerin with regard to blood pressure reduction. Co-administration of Nitroglycerin and Sacubitril / Valsartan was associated with a treatment difference of 5 bpm in heart rate compared to the administration of Nitroglycerin alone. A similar effect on the heart rate may occur when Sacubitril / Valsartan is co-administered with sublingual, oral or transdermal nitrates. In general no dose adjustment is required.

OATP and MRP2 transporters

The active metabolite of Sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; Valsartan is also a MRP2 substrate. Therefore, co-administration of Sacubitril / Valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. Rifampicin, Ciclosporin), OAT1 (e.g. Tenofovir, Cidofovir) or MRP2 (e.g. Ritonavir) may increase the systemic exposure of LBQ657 or Valsartan. Appropriate care should be exercised when initiating or ending concomitant treatment with such medicinal products.

Metformin

Co-administration of Sacubitril / Valsartan with metformin reduced both Cmax and AUC of Metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with Sacubitril / Valsartan in patients receiving metformin, the clinical status of the patient should be evaluated.

No significant interaction

No clinically meaningful drug-drug interaction was observed when Sacubitril / Valsartan was co-administered with Digoxin, Warfarin, Hydrochlorothiazide, Amlodipine, Omeprazole, Carvedilol or a combination of Levonorgestrel/Ethinyl Estradiol.

4.6 Special populations

Pregnancy

The use of Sacubitril / Valsartan is not recommended during the rst trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. There are no data from the use of Sacubitril / Valsartan in pregnant women. Animal studies with Sacubitril / Valsartan have shown reproductive toxicity.

Breast-feeding

It is not known whether Sacubitril / Valsartan is excreted in human milk. The components Sacubitril and Valsartan, were excreted in the milk of lactating rats. Because of the potential risk for adverse reactions in breast-fed new-borns/infants, it is not recommended during breast-feeding. A decision should be made whether to abstain from breast-feeding or to discontinue Zuvatan while breast-feeding, taking into account the importance of Sacubitril / Valsartan to the mother.

Fertility

There are no available data on the effect of Sacubitril / Valsartan on human fertility. No impairment of fertility was demonstrated in studies with it in male and female rats.

4.7 Effects on ability to drive and use machines

Sacubitril / Valsartan has a minor influence on the ability to drive and use machines. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.

4.8 Undesirable Effects

The most commonly reported adverse reactions during treatment with Sacubitril / Valsartan were hypotension, hyperkalaemia and renal impairment. Angioedema was reported in patients treated with Sacubitril / Valsartan.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Limited data are available with regard to overdose in humans. A single dose of 583 mg Sacubitril / 617 mg Valsartan and multiple doses of 437 mg Sacubitril / 463 mg Valsartan (14 days) were studied in healthy volunteers and were well tolerated. Hypotension is the most likely symptom of overdose due to the blood pressure lowering effects of Sacubitril / Valsartan. Symptomatic treatment should be provided. The medicinal product is unlikely to be removed by haemodialysis due to high protein binding.

5.1 Mechanism of action

Sacubitril / Valsartan exhibits the mechanism of action of an angiotensin receptor Neprilysin inhibitor by simultaneously inhibiting Neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug Sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via Valsartan. The complementary cardiovascular benefits of Sacubitril / Valsartan in heart failure patients are attributed to the enhancement of peptides that are degraded by Neprilysin, such as natriuretic peptides (NP), by LBQ657 and the simultaneous inhibition of the effects of angiotensin II by Valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), which could result in vasodilation, natriuresis and diuresis, increased glomerular fltration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects.

Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. This prevents sustained activation of the renin-angiotensin-aldosterone system that would result in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodelling.

5.2 Pharmacodynamic Properties

The pharmacodynamic effects of Sacubitril / Valsartan were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous Neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of Sacubitril / Valsartan resulted in an initial increase in natriuresis, increased urine cGMP, and decreased plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and Nterminal prohormone brain natriuretic peptide (NTproBNP) compared to valsartan. In a 21-day study in HFrEF patients, Sacubitril / Valsartan signicantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. The AT1-receptor was also blocked as evidenced by increased plasma renin activity and plasma renin concentrations. In the PARADIGM-HF study, Sacubitril / Valsartan decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with Enalapril. BNP is not a suitable biomarker of heart failure in patients treated with Sacubitril / Valsartan because BNP is a neprilysin substrate. NT-proBNP is not a Neprilysin substrate and is therefore a more suitable biomarker.

In a thorough QTc clinical study in healthy male subjects, single doses of Sacubitril / Valsartan 194 mg Sacubitril / 206 mg Valsartan and 583 mg Sacubitril / 617 mg Valsartan had no effect on cardiac repolarisation. Neprilysin is one of multiple enzymes involved in the clearance of amyloid- (A ) from the brain and cerebrospinal fluid (CSF). Administration of Sacubitril / Valsartan 194 mg Sacubitril / 206 mg Valsartan once daily for two weeks to healthy subjects was associated with an increase in CSF A 1-38 compared to placebo; there were no changes in concentrations of CSF A 1-40 and 1-42. The clinical relevance of this finding is not known

5.3 Pharmacokinetic properties

Absorption

Following oral administration, Sacubitril / Valsartan dissociates into valsartan and the prodrug Sacubitril. Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of Sacubitril and Valsartan is estimated to be more than 60% and 23%, respectively.

Following twice daily dosing of Sacubitril / Valsartan, steady-state levels of Sacubitril, LBQ657 and valsartan are reached in three days. At steady state, Sacubitril and Valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of Sacubitril, LBQ657 and valsartan. Sacubitril / Valsartan can be administered with or without food

Distribution

Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94 - 97%). Based on the comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%). The average apparent volume of distribution of Valsartan and Sacubitril were 75 litres to 103 litres, respectively.

Biotransformation

Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not further metabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite of Valsartan has been identified in plasma at low concentrations (< 10%). Since CYP450-enzyme-mediated metabolism of Sacubitril and Valsartan is minimal, co-administration with medicinal products that impact CYP450 enzymes is not expected to impact the pharmacokinetics. In vitro metabolism studies indicate that potential for CYP450 based drug interactions is low since there is limited metabolism of Sacubitril / Valsartan via CYP450 enzymes. Sacubitril / Valsartan does not induce or inhibit CYP450 enzymes.

Elimination

Following oral administration, 52 - 68% of Sacubitril (primarily as LBQ657) and ~13% of Valsartan and its metabolites are excreted in urine; 37 - 48% of Sacubitril (primarily as LBQ657) and 86% of valsar tan and its metabolites are excreted in faeces.

Sacubitril, LBQ657 and Valsartan are eliminated from plasma with a mean elimination half-life (T½) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.

6.1 Animal toxicology or pharmacology

Non-clinical data (including studies with Sacubitril and Valsartan components and/or Sacubitril / Valsartan) reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility.

Zuvatan (Sacubitril and Valsartan) is a combination of a Neprilysin inhibitor and an angiotensin II receptor blocker.

Following oral administration, the complex dissociates into Sacubitril (which is further metabolized to LBQ657) and Valsartan. The complex is chemically described as Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´- biphenyl]-4-ylmethyl)-4-ethoxy-3- methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis(N-pentanoyl-N-{[2´- (1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water (1/15).

Its empirical formula is C₄₈H₅₅N₆O₈Na₃ 2.5 H₂O. Its molecular mass is 957.99 g/mol and its schematic structural formula is

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Zuvatan 50 : Alu-Alu blister strip of 10 tablets.

Zuvatan 100 : Alu-Alu blister strip of 10 tablets.

Zuvatan 200 : Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions

Store below 30°C. Store in an original package in order to protect from moisture.

Keep out of reach of children.

What is Zuvatan ?

Zuvatan is a prescription medicine used to treat adults with long-lasting (chronic) heart failure to help reduce the risk of death and hospitalization. Zuvatan works better when the heart cannot pump a normal amount of blood to the body.

Pregnancy

Advise female patients of childbearing age about the consequences of exposure to Zuvatan during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible

Angioedema

Advise patients to discontinue use of their previous ACE inhibitor or ARB. Advise patients to allow a 36 hour wash-out period if switching from or to an ACE inhibitor.

What is the most important information I should know about Zuvatan ?

Zuvatan can harm or cause death to your unborn baby. Talk to your doctor about other ways to treat heart failure if you plan to become pregnant. If you get pregnant during treatment with Zuvatan, tell your doctor right away.

Do not take Zuvatan if you :

• Are allergic to any of the ingredients in Zuvatan. See the end of this Patient Information leaflet for a complete list of ingredients in Zuvatan.
• Have had an allergic reaction including swelling of your face, lips, tongue, throat, or trouble breathing while taking a type of medicine called an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).
• Take an ACE inhibitor medicine. Do not take Zuvatan for at least 36 hours before or after you take an ACE inhibitor medicine. Talk with your doctor or pharmacist before taking Zuvatan if you are not sure if you take an ACE inhibitor medicine.
• Have diabetes and take a medicine that contains Aliskiren.

Before taking Zuvatan, tell your doctor about all of your medical conditions, including if you :

• Have a history of hereditary angioedema.
• Have kidney or liver problems.
• Are pregnant or plan to become pregnant.
• Are breastfeeding or plan to breastfeed. It is not known if Zuvatan passes into your breast milk. You and your doctor should decide if you will take Zuvatan or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using Zuvatan with certain other medicines may affect each other. Using Zuvatan with other medicines can cause serious side effects.

Especially tell your doctor if you take :

• Potassium supplements or a salt substitute.
• Nonsteroidal anti-inflammatory drugs (NSAIDs).
• Lithium
• Other medicines for high blood pressure or heart problems such as an ACE inhibitor, ARB, or Aliskiren.

How should I take Zuvatan ?

• Take Zuvatan exactly as your doctor tells you to take it.
• Take Zuvatan 2 times each day. Your doctor may change your dose of Zuvatan during treatment.
• If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare Zuvatan as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will adjust the dose as needed. Shake the bottle of suspension well before measuring the dose of medicine to give to your child.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose,
• Do not take the missed dose. Take the next dose at your regular time.
• If you take too much Zuvatan, call your doctor right away.

15 February 2023