Plecanatide Tablets 3 mg

Each uncoated tablet contains :

Plecanatide 3 mg

Tablet 3 mg

4.1 Therapeutic indications

Indicated in adults for the treatment of

• Chronic idiopathic constipation (CIC)
• Irritable bowel syndrome with constipation (IBS-C)

4.2 Posology and method of administration

The recommended dosage of Plecasoft for the treatment of CIC and IBS-C is 3 mg taken orally once daily. Preparation and administration instructions

• Plecasoft can be taken with or without food.
• If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.
• Swallow a tablet whole for each dose.
• For adult patients with swallowing difficulties, Plecasoft tablets can be crushed and administered orally either in applesauce or with water or administered with water via a nasogastric or gastric feeding tube. Mixing Plecasoft crushed tablets in other soft foods or in other liquids has not been tested.

Oral administration in applesauce 

• In a clean container, crush the Plecasoft tablet to a powder and mix with 1 teaspoonful of room temperature applesauce.
• Consume the entire tablet-applesauce mixture immediately. Do not store the mixture for later use.

Oral administration in water

• Place the Plecasoft tablet in a clean cup.
• Pour approximately 30 mL of room temperature water into the cup.
• Mix by gently swirling the tablet and water mixture for at least 10 seconds. The Plecasoft tablet will fall apart in the water.
• Swallow the entire contents of the tablet water mixture immediately.
• If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 10 seconds, and swallow immediately.
• Do not store the tablet-water mixture for later use.

Administration with water via a nasogastric or gastric feeding tube

• Place the Plecasoft tablet in a clean cup with 30 mL of room temperature water.
• Mix by gently swirling the tablet and water mixture for at least 15 seconds. The Plecasoft tablet will fall apart in the water.
• Flush the nasogastric or gastric feeding tube with 30 mL of water using a catheter tip syringe.
• Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric feeding tube. Do not reserve for future use.
• If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 15 seconds, and using the same syringe, administer via the nasogastric or gastric feeding tube.
• Using the same or a fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water.

4.3 Contraindications

• Patients less than 6 years of age due to the risk of serious dehydration.
• Patients with known or suspected mechanical gastrointestinal obstruction.

4.4 Special warnings and precautions for use

Risk of serious dehydration in pediatric patients

Plecanatide is contraindicated in patients less than 6 years of age. The safety and effectiveness of Plecanatide in patients less than 18 years of age have not been established Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences. Avoid the use of Plecanatide in patients 6 years to less than 18 years of age. Diarrhea If severe diarrhea occurs, suspend dosing and rehydrate the patient.

4.5 Drugs interactions

Neither plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro. Plecanatide and its active metabolite were neither substrates nor inhibitors of the transporters Pglycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Pregnancy

Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. The available data on Plecanatide use in pregnant women are not sufficient to inform any drug associated risks for major birth defects and miscarriage. 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.

Lactation

There is no information regarding the presence of plecanatide in human milk, or its effects on milk production or the breastfed infant. Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration. It is unknown whether the negligible systemic absorption of plecanatide by adults will result in a clinically relevant exposure to breastfed infants. Exposure to plecanatide in breastfed infants has the potential for serious adverse effects. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Plecanatide and any potential adverse effects on the breastfed infant from Plecanatide or from the underlying maternal condition.

Pediatric use

Plecanatide is contraindicated in pediatric patients less than 6 years of age. Avoid use of Plecanatide in patients 6 years to less than 18 years of age. The safety and effectiveness of Plecanatide in patients less than 18 years of age have not been established. Because of increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop diarrhea and its potentially serious consequences. Plecanatide is contraindicated in patients less than 6 years of age.

Geriatric use

The safety and effectiveness of Plecanatide in patients greater than 65 years of age have not been established.

4.7 Effects on ability to drive and use machines

Plecanatide has no or negligible influence on the ability to drive and use machines. During treatment with Plecanatide, dizziness has been reported as less common adverse reaction. Therefore, patients who experience dizziness should be cautious while driving or using machines.

4.8 Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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.co.in/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific treatment to the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required.

5.1 Mechanism of action

Plecanatide is a structural analog of human uroguanylin, and similarly to uroguanylin, plecanatide functions as a guanylate cyclase-C (GC-C) agonist. Both plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of extracellular cGMP has been associated with a decrease in the activity of pain-sensing nerves in animal models of visceral pain. Elevation of intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic brosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.

5.2 Pharmacodynamic properties

Food effect

Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after a single dose of plecanatide 9 mg (3 times the recommended dose). In clinical studies, plecanatide was administered with or without food.

5.3 Pharmacokinetic properties

Absorption

Plecanatide was minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma were below the limit of quantitation in the majority of analyzed plasma samples after an oral plecanatide dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, Cmax, and half-life (t1/2) could not be calculated.

Distribution

Given that plecanatide concentrations following clinically relevant oral doses were not measurable, plecanatide is expected to be minimally distributed in tissues. Oral plecanatide was localized to the GI tract where it exerted its effects as a GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human α-1-acid glycoprotein.

Metabolism

Plecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Excretion

Plecanatide and its active metabolite were not measurable in plasma following administration of the recommended clinical doses.

6.1 Animal toxicology or pharmacology

The carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Limited systemic exposure to plecanatide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay. Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day.

Plecasoft (plecanatide) is a guanylate cyclase-C (GC-C) agonist. Plecanatide is a 16 amino acid peptide with the following chemical name : L-Leucine, L-asparaginyl-L-α-aspartyl-L-α-glutamyl-L-cysteinyl-L-α-glutamyl-L-leucyl-L-cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-, cyclic (4 12), (7 15)-bis (disufide).The molecular formula of plecanatide is C65H104N18O26S4 and the molecular weight is 1682 Daltons.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handling instructions

Store at a temperature below 25°C.

Keep out of reach of children.

Advise patients :

Diarrhea

To stop Plecasoft and contact their healthcare provider if they experience severe diarrhea.

Accidental ingestion

Accidental ingestion of Plecasoft in children, especially in children less than 6 years of age, may result in severe diarrhea and dehydration. Instruct patients to take steps to store Plecasoft securely and out of reach of children and to dispose of unused Plecanatide.

Administration and handling instructions 

• To take Plecasoft once daily with or without food
• If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.
• To swallow Plecasoft tablets whole.
• If adult patients have swallowing difficulties, Plecasoft tablets can be crushed and administered orally in either applesauce or with water, or administered with water via a nasogastric or gastric feeding tube. • To keep Plecasoft in a dry place. Protect from moisture. For bottles, keep Plecasoft in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. Remove and discard polyester coil after opening. Keep bottles closed tightly.

21 January 2025

Fluticasone Furoate & Oxymetazoline Hydrochloride Nasal Spray

Each spray delivers :

Fluticasone Furoate 27.5 mcg

Oxymetazoline Hydrochloride IP 50 mcg

Composition :

Fluticasone Furoate 0.028% w/w

Oxymetazoline Hydrochloride IP 0.050% w/w

Benzalkonium Chloride Solution IP 0.030% w/w

Nasal Spray, Fluticasone Furoate 27.5 mcg & Oxymetazoline Hydrochloride 50 mcg

4.1 Therapeutic indication

For the treatment of symptoms of allergic rhinitis with nasal congestion.

4.2 Posology and method of administration

The recommended dose is two spray actuations (27.5 micrograms of. Fluticasone Furoate and 50 mcg of Oxymetazoline Hydrochloride per spray actuation) in each nostril once daily (total daily dose, 110 micrograms of Fluticasone Furoate and 200 mcg of Oxymetazoline Hydrochloride). Once adequate control of symptoms is achieved, dose reduction to one spray actuation in each nostril (total daily dose 55 micrograms of Fluticasone Furoate and 100 mcg of Oxymetazoline Hydrochloride) may be effective for maintenance.

Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray is for administration by the intranasal route only.

The intranasal device should be shaken before use. The device is primed by pressing the mist release button for at least six spray actuations (until a fine mist is seen), whilst holding the device upright. Re-priming (approximately 6 sprays until a fine mist is seen) is only necessary if the cap is left off for 5 days or the intranasal device has not been used for 30 days or more.

Children < 12 years of age

Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray should not be used in children less than 12 years of age.

Elderly (≥ 65 years old)

No dose adjustment is required in this population.

Renal impairment

No dose adjustment is required in this population.

Hepatic impairment

No dose adjustment is required in this population.

4.3 Contraindications 

• Hypersensitivity to Fluticasone Furoate, Oxymetazoline or any other ingredients of this medicine.
• Age less than 12 years.
• In patients who have undergone recent trans-nasal surgery.
• In patients with chronic nasal inammation with very dry nasal passages (rhinitis sicca or atrophic rhinitis).
• In patients with cardiovascular disease, hyperthyroidism, angle closure glaucoma or prostatic enlargement.

4.4 Special warnings and precautions for use

Keep the spray away from the eyes.

Systemic corticosteroid effects

Systemic effects of nasal corticosteroid may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely tooccur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used, then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. Fluticasone furoate 110 micrograms once daily has not been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression in adult or adolescent subjects. However, the dose of intranasal fluticasone furoate should be reduced to the lowest dose at which effective control of the symptoms of rhinitis is maintained. As with all intranasal corticosteroids, the total systemic burden of corticosteroids should be considered whenever other forms of corticosteroid treatment are prescribed concurrently. If there is any reason to believe that adrenal function is impaired, care must be taken when transferring patients from systemic steroid treatment to fluticasone furoate.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient present with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Growth retardation

Growth retardation has been reported in children receiving nasal corticosteroids at licensed doses. A reduction in growth velocity has been observed in children treated with fluticasone furoate 110 micrograms daily for one year. Therefore, children should be maintained on the lowest possible efficacious dose which delivers adequate symptom control. It is recommended that the growth of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of nasal corticosteroid if possible, to the lowest dose at which effective control of symptoms is maintained.

Patients on ritonavir

Concomitant administration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone Furoate.

4.5 Drug interactions

Interaction with CYP3A inhibitors

Fluticasone furoate is rapidly cleared by extensive first-pass metabolism mediated by the cytochrome P450 3A4.

Based on data with another glucocorticoid (fluticasone propionate), that is metabolised by CYP3A4, coadministration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone furoate. Caution is recommended when co-administering fluticasone furoate with potent CYP3A inhibitors including cobicistat containing products as an increase in the risk of systemic side effects is expected. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid side effects. In a drug interaction study of intranasal fluticasone furoate with the potent CYP3A4 inhibitor ketoconazole there were more subjects with measurable fluticasone furoate concentrations in the ketoconazole group (6 of the 20 subjects) compared to placebo (1 out of 20 subjects). This small increase in exposure did not result in a statistically significant difference in 24-hour serum cortisol levels between the two groups.

The enzyme induction and inhibition data suggest that there is no theoretical basis for anticipating metabolic interactions between fluticasone furoate and the cytochrome P450 mediated metabolism of other compounds at clinically relevant intranasal doses. Therefore, no clinical studies have been conducted to investigate interactions of fluticasone furoate on other drugs Monoamine oxidase inhibitors (MAOIs), nonselective beta adrenergic antagonists, or tricyclic antidepressants.

Use of Oxymetazoline containing nasal spray in combination with monoamine oxidase inhibitors (MAOIs), nonselective beta adrenergic antagonists, or tricyclic antidepressants may cause hypertension and is not recommended.

4.6 Use in special populations

Pregnancy

There are no adequate data from the use of fluticasone furoate and Oxymetazoline containing nasal sprays in pregnant women. In animal studies glucocorticoids have been shown to induce malformations including cleft palate and intra-uterine growth retardation. This is not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure.

Breast-feeding

It is unknown whether nasal administered fluticasone furoate or Oxymetazoline is excreted in human breast milk. Administration of Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray to women who are breast-feeding should only be considered if the expected benet to the mother is greater than any possible risk to the child.

Fertility

There are no fertility data in humans.

4.7 Effects on ability to drive and use machines

Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The most common AEs reported with the use of Fluticasone Furoate and Oxymetazoline containing Nasal Spray are epistaxis, nasal ulceration, nasal dryness & discomfort, sneezing and headache. The other AEs include : rhinalgia, transient ocular changes, vision blurred, nasal septum perforation, dry mouth, stomatitis, dry throat, local irritation, insomnia, sedation, anxiety, irritability, nausea, hypertension, irregular heart rate, increased heart rate, restlessness, somnolence, fatigue, hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria. Prolonged use may cause rebound congestion and rhinitis medicamentosa.

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.co.in/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Overdosage may give rise to local irritation and rebound congestion. Treatment need only be symptomatic

5.1 Pharmacodynamic properties

Fluticasone furoate is a synthetic tri-fluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action.

Oxymetazoline is a direct-acting sympathomimetic amine. It acts on alpha-adrenergic receptors in the vessels of the nasal mucosa producing vasoconstriction and decongestion.

5.2 Pharmacokinetic properties

Fluticasone Furoate

Absorption: Fluticasone furoate undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily does not typically result in measurable plasma concentrations (<10 pgl ml). The absolute bioavailability for intranasal uticasone furoate is 0.50 %, such that less than 1 microgram of fluticasone furoate would be systemically available after administration of 110 micrograms

Distribution: The plasma protein binding of fluticasone furoate is greater than 99%. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 L.

Biotransformation: Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 I/h) from systemic circulation principally by hepatic metabolism to an inactive 17p-carboxylic metabolite (GW694301X), by the cytOchrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 1713- carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.

Elimination: Elimination is primarily via the faecal route following oral and intravenous administration indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1 % and 2 % of the orally and intravenously administered dose, respectively.

Oxymetazoline Hydrochloride

Oxymetazoline enters tissues rapidly and local vasoconstriction is normally achieved within 5-10 minutes of intranasal administration. The full effect lasts for 5-6 hours and then gradually subsides over the next 6 hours. Plasma half-life is 5-8 days with 30% of any absorbed drug being excreted in the urine unchanged and 10% being excreted in the faeces

6.1 Animal Toxicology or pharmacology

Fluticasone Furoate

Findings in general toxicology studies were similar to those observed with other glucocorticoids and are associated with exaggerated pharmacological activity. These findings are not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure. No genotoxic effects of fluticasone furoate have been observed in conventional genotoxicity tests. Further, there were no treatment-related increases in the incidence of tumours in two-year inhalation studies in rats and mice.

Oxymetazoline Hydrochloride

There are no preclinical data of relevance

Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray is white to off white suspension in a pre-filled intranasal sprayer. The pH of suspension is 5.0 ± 1.0 The product contains two active ingredients : Fluticasone Furoate and Oxymetazoline Hydrochloride.

The chemical name of fluticasone Furoate is (6a,1113,16a,17a)-6,9- diuoro-17-{[(uoro-methypthioicarbony1}-11-hydroxy-16-methyl-3- oxoandrosta-1,4-dien-17-y1 2-furancarboxylate. The molecular weight is 538.6.

The chemical formula of Oxymetazoline Hydrochloride is 3-[(4,5- dihydro1H-imidazol-2-yOmethyl]-6-(1,1 ,-dimethylethyl)-2,4- dimethylphenol mono-hydrochloride. Its molecular weight is 296.8 for the hydrochloride salt and 260.4 for the free base.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

FLORESP-OX sales pack contains 7 gm (70 metered doses).

8.4 Storage and handling instructions

Store in a dry & dark place at a temperature not exceeding 25°C.

Keep out of reach of children.

• Keep the spray away from the eyes.
• Prolonged use of spray may lead to systemic corticosteroid effects. Consult your physician for duration of use of the product.
• Do not use the product in children less than 12 years of age
• Do not use the product if you have cardiovascular disease, hyperthyroidism, angle closure glaucoma or prostatic enlargement Do not use the product if you have undergone recent trans-nasal surgery, or in case of chronic nasal inflammation with very dry nasal passages (rhinitis sicca or atrophic rhinitis).

30 September 2024