Zofran - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Ondansetron

ZOFRAN 4 mg Film-coated tablets
ZOFRAN 8 mg Film-coated tablets
ZOFRAN 4 mg Orodispersible tablets
ZOFRAN 8 mg Orodispersible tablets
ZOFRAN 4 mg / 2 ml Solution for injection
ZOFRAN 8 mg / 4 ml Solution for injection
ZOFRAN 40 mg / 20 ml Solution for injection
ZOFRAN 4 mg / 5 ml Syrup
ZOFRAN 16 mg Suppositories

Why is Zofran used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

Antiemetics and antinauseants - serotonin antagonists (5HT3).

THERAPEUTIC INDICATIONS

Adults

Control of nausea and vomiting induced by antiblastic chemotherapy and radiotherapy; prophylaxis and treatment of post-operative nausea and vomiting (PONV).

Pediatric population:

Zofran is indicated for the control of chemotherapy induced nausea and vomiting (CINV) in children 6 months of age and older, and for the prevention and treatment of PONV in children 1 month and older.

Contraindications When Zofran should not be used

Hypersensitivity to the active substance or to any of the excipients. Based on reports documenting reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Pregnancy; breastfeeding (see "Special warnings").

Due to the presence of aspartame, ZOFRAN Orodispersible tablets is contraindicated in patients with phenylketonuria.

Precautions for use What you need to know before you take Zofran

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists.

Respiratory reactions should be treated with symptoms and physicians should pay particular attention to them as they may be precursors of hypersensitivity reactions. Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, cases of Torsade de Pointes have been reported in patients treated with ondansetron during the post-marketing phase.

Avoid administration of ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop QTc prolongation. These conditions include patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmia, or patients taking other medicines that lead to QT prolongation or electrolyte disturbances. Therefore, caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic or beta-blocking agents, and in patients with significant electrolyte disturbances.

Hypokalaemia and hypomagnesaemia must be corrected prior to administration of ondansetron. Cases of serotonin syndrome with the use of serotonin (5-HT3) antagonists have been reported, either alone but especially in combination with other serotonergic drugs (including selective reuptake inhibitors serotonin (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI).

As ondansetron is known to increase the transit time of the large intestine, patients with symptoms of subacute intestinal obstruction receiving ondansetron should be monitored.

Prevention of nausea and vomiting with ondansetron may mask occult bleeding in patients who have undergone adenotonsillar surgery. Consequently, such patients should be followed closely after ondansetron administration.

Pediatric population:

Pediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be closely monitored for hepatic insufficiency.

Chemotherapy induced nausea and vomiting: When calculating the dose on an mg / kg basis and administering three doses at 4 hour intervals, the total daily dose will be higher than when administering a single dose of 5 mg / m2. The comparative efficacy of these two different dosage regimens has not been investigated in clinical studies. A cross-comparison indicates similar efficacy for both regimens.

Interactions Which drugs or foods may change the effect of Zofran

Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription. There is no evidence that ondansetron induces or inhibits the metabolism of other drugs usually administered concurrently. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolizing ondansetron, enzyme inhibition or reduced activity of one enzyme (eg genetic deficiency of CYP2D6) is generally compensated by other enzymes and the total clearance of ondansetron or the required dosage must undergo slight or insignificant changes.

Caution is required if ondansetron is administered in combination with drugs that prolong the QT interval and / or cause electrolyte abnormalities (see "Precautions for use"). Use of Zofran with drugs that prolong the QT interval may result in further prolongation. Concomitant use of Zofran with cardiotoxic drugs (anthracyclines such as doxorubicin and daunorubicin, or trastuzumab), antibiotics (such as erythromycin), ketoconazole, antiarrhythmics (such as amiodarone) and beta-blockers (such as atenolol or timolol) may increase the risk arrhythmias (see "Usage Precautions").

Apomorphine

Based on reports documenting reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Phenytoin, carbamazepine and rifampicin

In patients treated with potent CYP3A4 inducers (e.g. phenytoin, carbamazepine and rifampicin) the oral clearance of ondansetron was increased and ondansetron plasma concentrations decreased.

Serotonergic drugs (e.g. empioSSRIs and SNRIs):

Cases of serotonin syndrome have been reported following the concomitant use of serotonin (5-HT3) antagonists and other serotonergic drugs (including SSRIs and SNRIs).

Tramadol

Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Warnings It is important to know that:

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy

The safety of ondansetron in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects on embryo-fetal development, gestation and peri- and postnatal development. However, as animal studies are not always predictive of human responses, ondansetron must not be administered during pregnancy.

Feeding time

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers being treated with ondansetron do not breastfeed.

Effects on ability to drive and use machines

In psychomotor tests, ondansetron does not modify performance, nor does it cause sedation. Based on the pharmacology of ondansetron, no harmful effects on these activities are expected.

Important information about some of the excipients

Zofran film-coated tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

ZOFRAN 4 mg Orodispersible tablets contains small amounts of ethanol less than 100 mg per dose (may contain up to 0.0015 mg of ethanol) and ZOFRAN 8 mg Orodispersible tablets contains small amounts of ethanol less than 100 mg per dose (may contain up to 0.003 mg of ethanol).

Zofran orodispersible tablets contain aspartame, a source of phenylalanine. They can be harmful if you have phenylketonuria.

Zofran orodispersible tablets contain methyl parahydroxybenzoate and propyl parahydroxybenzoate. It can cause allergic reactions (even delayed).

Zofran 40 mg / 20 ml solution for injection contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. It can cause allergic reactions (even delayed) and, exceptionally, bronchospasm.

Zofran 40 mg / 20 ml solution for injection contains sodium (0.25 mg / ml as sodium citrate and 8.30 mg / ml as sodium chloride). To be taken into consideration in people on a low sodium diet.

Zofran syrup contains sorbitol. Patients with rare hereditary fructose problems should not take this medicine.

Zofran syrup contains sodium (7.5 mg as sodium citrate and 10 mg as sodium benzoate) per dose (from 5 ml). To be taken into consideration in people on a low sodium diet.

Dosage and method of use How to use Zofran: Dosage

Nausea and vomiting induced by chemotherapy (CINV) and radiotherapy (RINV)

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The choice of dose regimen should be determined by the severity of the emesis.

ZOFRAN can be administered orally (Tablets, Orodispersible Tablets, Syrup), by intravenous or intramuscular injection (Solution for injection), or rectally (Suppositories).

Populations

CINV and RINV in adults:

Initial treatment

The usual dosage is 8 mg before chemotherapy or radiotherapy administered as follows: -

  • Solution for injection: 8 mg intravenously slowly (in not less than 30 seconds) or intramuscularly, immediately before treatment;
  • Tablets / Orodispersible Tablets: 8 mg taken 1 to 2 hours prior to chemotherapy or radiotherapy treatment, followed by 8 mg orally every 12 hours for up to 5 days;
  • Syrup: 10 ml (8 mg) 2 hours before treatment.

In cases of highly emetogenic chemotherapy, corticosteroid therapy may be associated.

Alternatively, a 16 mg suppository can be used to be administered 1-2 hours before treatment. In some cases (use of highly emetizing cytotoxic drugs and / or prescribed at very high doses; presence of factors related to the patient, such as young, female subjects or with previous emetic phenomena during previous cytotoxic treatments) it is possible to use:

  • A single 8 mg dose by slow intravenous injection (over not less than 30 seconds) or intramuscularly immediately prior to chemotherapy.
  • One dose of 8 mg by slow intravenous injection (over not less than 30 seconds) or intramuscular injection immediately before chemotherapy, followed by two further intravenous injections (over not less than 30 seconds) or intramuscular doses of 8 mg four hours apart one on the other, or with a constant infusion of 1mg / hour up to 24 hours.
  • a maximum starting dose of 16 mg diluted in 50-100 ml of sodium chloride 9 mg / ml (0.9%) solution for injection or other compatible infusion fluid (see section 6.6) and administered by infusion, for at least 15 minutes immediately before chemotherapy treatment).

The initial dose of Zofran can be followed by two further 8 mg intravenous doses (in no less than 30 seconds) or intramuscular doses 4 hours apart.

A single dose greater than 16 mg should not be administered due to the dose-dependent increased risk of QT interval prolongation (see Precautions for use and Undesirable Effects).

The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by the administration of a single 20 mg intravenous dose of dexamethasone sodium phosphate, administered prior to chemotherapy.

Continuation of therapy (prevention of delayed or prolonged emesis)

8 mg of ondansetron orally (tablets, orodispersible tablets, syrup) every 12 hours, or a suppository of 16 mg per day in the following days, for an average duration of 2 to 3 days, with the possibility of continuing up to 5 days.

Pediatric population:

CINV in children 6 months of age and older and adolescents

The dose for CINV should be calculated by body surface area (BSA) or by weight - see below. Calculating by weight results in higher doses than calculating by body surface area (see "Precautions for" use ").

The ondansetron injection must be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion solutions (see "Instructions for use and handling") and administered intravenously in no less than 15 minutes.

There are no data from controlled clinical trials on the use of Zofran in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of Zofran in radiotherapy induced nausea and vomiting in children.

Dosage according to BSA:

Zofran should be administered immediately prior to chemotherapy as a single intravenous dose of 5 mg / m2. The single intravenous dose should not exceed 8 mg. Oral administration can commence 12 hours later and can be continued for up to 5 days (Table 1). The total 24 hour dose (given in single doses) should not exceed the adult dose of 32 mg.

Table 1: Chemotherapy Dosage Based on BSA - Children aged ≥6 months and adolescents


BSA Day 1 (a, b) Days 2-6 (b) <0.6 m2 5 mg / m2 i.v. 2 mg syrup after 12 hours 2 mg syrup every 12 hours > 0.6 m2 5 mg / m2 i.v. 4 mg syrup or tablets after 12 hours 4 mg syrup or tablets every 12 hours

a The intravenous dose should not exceed 8 mg

b The total 24 hour dose should not exceed adult dose of 32 mg

Dosage based on body weight:

Weight-based dosing results in a higher total daily dose compared to BSA dosing (see "Precautions for use"). Zofran should be administered immediately prior to chemotherapy as a single intravenous dose of 0.15 mg / kg The intravenous dose should not exceed 8 mg Two further intravenous doses may be administered at 4 hour intervals The total 24 hour dose should not exceed adult dose of 32 mg.

Oral dosing can begin 12 hours later and can continue for up to 5 days (Table 2).

Table 2: Dosage for chemotherapy based on body weight - Children aged ≥6 months and adolescents


Body weight Day 1 (a, b) Days 2-6 (b) ≤10 kg Up to three doses of 0.15 mg / kg every 4 hours 2 mg syrup every 12 hours > 10 kg Up to three doses of 0.15 mg / kg every 4 hours 4 mg syrup or tablets every 12 hours

a The intravenous dose should not exceed 8 mg

b The total 24 hour dose should not exceed adult dose of 32 mg

Zofran can be administered as a single intravenous injection of 5 mg / m2, immediately prior to chemotherapy, followed by 4 mg orally (1 Tablet / Orodispersible Tablet or 5 ml Syrup) after 12 hours.

This regimen should be followed by oral therapy (tablets / orodispersible tablets or syrup) at a dosage of 4 mg (5 ml of syrup) twice a day, up to 5 days after the treatment cycle.

Suppositories

The use of ondansetron suppositories is not recommended in children. The usual route of administration is intravenous followed by oral therapy (see Pediatric population - "Solution for injection" and "Oral formulations").

Elderly patients

In patients aged 65 to 74 years, the adult dosing schedule can be followed. All intravenous doses should be diluted in 50 - 100 ml of saline or other compatible infusion fluids (see section 6.6) and infused over not less than 15 minutes.

In patients 75 years of age or older, the initial intravenous dose of Zofran should not exceed 8 mg.

All intravenous doses should be diluted in 50 - 100 ml of saline or other compatible infusion fluids (see section 6.6) and infused over not less than 15 minutes.

The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg each, infused over not less than 15 minutes and not less than 4 hours apart (see section 5.2).

Patients with renal insufficiency

No adjustment of dosage or frequency or route of administration is necessary.

Patients with hepatic insufficiency

In subjects with moderate or severe impairment of hepatic function, the clearance of ondansetron is significantly reduced and the serum half-life is significantly increased. In such patients the total daily dose of 8 mg should not be exceeded and therefore administration per day is recommended. orally or parenterally.

Post-operative nausea and vomiting (PONV)

Use in the indication post-operative nausea and vomiting is reserved for hospital use. ZOFRAN can be administered orally (tablets / orodispersible tablets or syrup) or by intravenous or intramuscular injection.

Adults

For the prophylaxis of post-operative nausea and vomiting, ZOFRAN can be administered as a single 4 mg dose by intramuscular or slow intravenous injection upon induction of anesthesia or orally as a single dose of 16 mg (2 orodispersible tablets / tablets or 20 ml of syrup), one hour before the anesthesia.

For the treatment of post-operative nausea and vomiting, when already established, a single dose of 4 mg administered by slow intramuscular or intravenous injection is recommended.

Pediatric population:

Prevention of post-operative nausea and vomiting (PONV) in children aged ≥1 month and adolescents

Injectable solution

For the prevention of PONV in pediatric patients undergoing surgery under general anesthesia, ondansetron can be administered as a single dose by slow intravenous injection (over not less than 30 seconds) at a dose of 0.1 mg / kg up to a maximum dose. of 4 mg either before, during or after induction of anesthesia, or after surgery. For the treatment of PONV in pediatric patients undergoing surgery under general anesthesia, ondansetron can be administered as a single dose, by intravenous injection. slow (in not less than 30 seconds), at a dose of 0.1 mg / kg up to a maximum dose of 4 mg.

There are no data on the use of Zofran in the treatment of PONV in children less than 2 years of age.

Oral formulations

PONV in children aged ≥1 month and adolescents: No studies have been performed on the use of orally administered ondansetron in prophylaxis or in the treatment of post-operative nausea and vomiting: a slow intravenous injection is recommended for this purpose. there are data on the use of Zofran in the treatment of PONV in children less than 2 years of age.

Senior citizens

Experience with the use of ZOFRAN in the prophylaxis and treatment of postoperative nausea and vomiting in the elderly is limited. However, ZOFRAN is well tolerated in patients over 65 years of age receiving chemotherapy.

Patients with renal insufficiency

No adjustment of dosage or frequency or route of administration is necessary.

Patients with hepatic insufficiency

In subjects with moderate or severe impairment of hepatic function, the clearance of ondansetron is significantly reduced and the serum half-life is significantly increased. In such patients a total daily dose of 8 mg should not be exceeded, and therefore administration is recommended. orally or parenterally.

Patients with insufficient metabolic oxidative capacities of Sparteine ​​/ Debrisoquine

The elimination half-life of ondansetron is not modified in subjects with insufficient metabolic oxidative capacities of Sparteine ​​/ Debrysoquine. Therefore in such patients repeated doses will result in drug exposure levels that do not differ from those of the general population. No changes are therefore required. the dosage or frequency of administration.

Incompatibility

Oral formulations and suppositories

None .

Injectable solution

Ondansetron for injectable use must not be administered, like other drugs, in the same syringe or infusion fluid with other active substances (see "Instructions for use and handling").

Ondansetron for injectable use should only be administered in the recommended infusion solutions (see "Instructions for use and handling").

INSTRUCTIONS FOR USE AND HANDLING

ZOFRAN 4 mg Orodispersible tablets and ZOFRAN 8 mg Orodispersible tablets

Do not extract the tablets by pressing through the laminate. Peel off the backing foil of a blister and gently remove the tablet. Place the tablet on the tip of the tongue, where it will dissolve in a few moments, then swallow.

ZOFRAN 4 mg / 2 ml Injection Solution and ZOFRAN 8 mg / 4 ml Injection Solution (packed in ampoules, free of preservatives)

ZOFRAN Solution for injection must not be subjected to autoclaving.

Compatibility with infusion solutions

In accordance with the rules of good pharmaceutical practice, the intravenous solutions must be prepared at the time of infusion.

However, the preservative-free Ondansetron solution for injection has been shown to be stable for 7 days at room temperature (below 25 ° C) under fluorescent light or in the refrigerator with the following infusion solutions:

  • Sodium chloride for intravenous infusion 0.9% w / v
  • Glucose solution for intravenous infusion 5% w / v
  • Mannitol for intravenous infusion 10% w / v
  • Ringer's solution for intravenous infusion
  • Potassium chloride 0.3% w / v and sodium chloride 0.9% w / v for intravenous infusion
  • Potassium chloride 0.3% w / v and glucose 5% w / v for intravenous infusion

Compatibility studies were performed using PVC infusion bags and sets. It is believed that an "adequate stability of Ondansetron is possible using also polyethylene infusion bags or type I glass bottles. The solution for injection without preservatives diluted in 0.9% w / v physiological solution in 5% w / v glucose solution is it is also shown to be stable in polypropylene syringes. It is therefore believed that the preservative-free injectable solution, diluted with the other infusion solutions previously indicated as compatible, is also stable in polypropylene syringes. Note: Preparations must be prepared under aseptic conditions if extended storage periods are required

Compatibility with other drugs

Ondansetron can be administered by venous infusion at a dosage of 1 mg / hour eg with an infusion bag or with a plunger pump. The administration of the following drugs is compatible with Ondansetron at concentrations from 16 to 160 mcg / ml (eg . 8 mg in 500 ml and 8 mg in 50 ml respectively) using a Y set:

Cisplatin

Concentrations up to 0.48 mg / ml (eg 240 mg in 500 ml) administered over a period ranging from 1 to 8 hours.

5-Fluorouracil

Concentrations up to 0.8 mg / ml (e.g. 2.4 g in 3 liters or 400 mg in 500 ml) administered at a rate of at least 20 ml per hour (500 ml for 24 hours). Higher concentrations of 5-Fluorouracil can cause precipitation of Ondansetron. The 5-Fluorouracil infusion solution may contain up to 0.045% w / v of Magnesium Chloride in addition to other proven compatible excipients.

Carboplatin

Concentrations ranging from 0.18 mg / mL to 9.9 mg / mL (e.g. 90 mg in 500 mL up to 990 mg in 100 mL) can be administered over a period ranging from 10 minutes to 1 hour.

Etoposide

Concentrations ranging from 0.144 mg / mL to 0.25 mg / mL (eg 72 mg in 500 mL up to 250 mg in 1 liter) can be administered over a period of 30 min. and 1 hour.

Ceftazidime

Dosages ranging from 250 mg to 2000 mg reconstituted with water p.p.i., as recommended by the manufacturer (2.5 ml for 250 mg and 10 ml for 2 g of Ceftazidime), can be administered as an intravenous bolus over approximately 5 minutes.

Cyclophosphamide

Dosages between 100 mg and 1 g, reconstituted with water p.p.i., 5 ml per 100 mg of cyclophosphamide, as recommended by the manufacturer, can be administered as an intravenous bolus over approximately 5 minutes.

Doxorubicin

Dosages between 10 and 100 mg, reconstituted with water p.p.i., 5 ml per 10 mg of Doxorubicin, as recommended by the manufacturer, can be administered as an intravenous bolus over approximately 5 minutes.

Dexamethasone

20 mg of dexamethasone sodium phosphate can be given by slow intravenous injection over 2-5 minutes using a Y infusion set that releases 8 to 16 mg of Ondansetron over approximately 15 minutes, diluted in 50-100 ml of a compatible infusion fluid. The compatibility between dexamethasone sodium phosphate and Ondansetron has been demonstrated allowing the administration of the two drugs through the same set at concentrations of 32 µg-2.5 mg / ml for dexamethasone sodium phosphate and from 8 µg-1 mg / ml for l " Ondansetron.

ZOFRAN 40 mg / 20 ml Solution for injection - (Multidose bottle, with preservatives)

Compatibility studies were performed using PVC infusion bags and sets. It is believed that an "adequate stability of" ondansetron is possible using also polyethylene infusion bags or type I glass bottles.

The solution for injection without preservatives diluted in 0.9% w / v physiological solution or in 5% w / v glucose solution has been shown to be stable even in polypropylene syringes. It is therefore believed that the ondansetron injectable solution with or without preservatives, diluted with the compatible infusion solutions indicated below, is also stable in polypropylene syringes. Note: Preparations must be prepared under aseptic conditions if extended storage periods are required.

Compatibility with infusion solutions

In accordance with the rules of good pharmaceutical practice, the intravenous solutions must be prepared at the time of infusion.

However, the Ondansetron solution for injection with preservatives has been shown to be stable for 48 hours at room temperature (below 25 ° C) with the following infusion solutions:

  • Sodium chloride for intravenous infusion 0.9% w / v
  • Sodium chloride for intravenous infusion 3% w / v
  • Glucose solution for intravenous infusion 5% w / v
  • Sodium chloride 0.9% w / v and glucose solution for intravenous infusion 5% w / v
  • Sodium chloride 0.45% w / v and glucose solution for intravenous infusion 5% w / v

In line with the medicinal product packaged in ampoules (without preservatives - see above) it is believed that adequate stability is maintained even with the following infusion solutions, although compatibility studies with these solutions have not been performed:

  • Mannitol for intravenous infusion 10% w / v
  • Ringer's solution for intravenous infusion
  • Potassium chloride 0.3% w / v and sodium chloride 0.9% w / v for intravenous infusion
  • Potassium chloride 0.3% w / v and glucose 5% w / v for intravenous infusion.

Compatibility with other drugs

Ondansetron, diluted with a compatible infusion solution, can be administered by venous infusion at a dosage of 1 mg / hour, e.g. with an infusion bag or plunger pump. The following drugs can be co-administered, using a Y-set:

Cisplatin: concentrations up to 0.5 mg / ml (e.g. 250 mg in 500 ml) administered over a period ranging from 1 to 8 hours using a Y infusion set that releases Ondansetron concentrations from 3 to 150 µg / ml (e.g. . 1.5 mg / 500 ml and 7.5 mg / 50 ml, respectively).

Dexamethasone sodium phosphate: 20 mg administered by slow intravenous injection over 2-5 minutes using a Y-set that releases Ondansetron 8 to 16 mg ondansetron over approximately 15 minutes, diluted in 50-100 ml of a compatible infusion fluid.

Instructions for opening the vial

ZOFRAN 4 mg / 2 ml Solution for injection and ZOFRAN 8 mg / 4 ml Solution for injection

The vials are equipped with a safety pre-opening and must be opened as follows:

  • hold the lower part of the vial with one hand as shown in figure 1;
  • place the other hand on the upper part by placing the thumb over the COLORED DOT and exert pressure as indicated in figure 2.

Overdose What to do if you have taken too much Zofran

Signs and symptoms

Experience with overdose with ondansetron is limited. In most cases the symptoms were similar to those already reported in patients given the recommended doses (see "Side Effects"). Manifestations that have been reported include visual disturbances, severe constipation, hypotension, and a vasovagal episode with transient and second-degree atrioventricular block.

Ondansetron prolongs the QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.

Treatment

There is no specific antidote for ondansetron; therefore, in cases of suspected overdose, "appropriate symptomatic and supportive therapy should be administered. The use of Ipecac for the treatment of ondansetron overdose is not recommended as patient response is unlikely due to the antiemetic action of" ondansetron itself. If you have accidentally swallowed / taken an overdose of ZOFRAN, notify your doctor immediately or go to the nearest hospital. If you have any further questions on the use of ZOFRAN, ask your doctor or pharmacist.

Side Effects What are the side effects of Zofran

Like all medicines, ZOFRAN can cause side effects, although not everybody gets them.

Side effects are listed below by organ, system / system and by frequency.

Frequencies are defined as: very common (> 1/10), common (> 1/100 and 1/1000 and 1/10000 and <1/1000) and very rare (<1/10000), not known (the frequency cannot be established from the available data The following frequencies are estimated based on the recommended standard doses of ondansetron, depending on the indication and formulation.

Disorders of the immune system

Rare: immediate hypersensitivity reactions, sometimes severe, including anaphylactic reactions

Nervous system disorders

Very common: headache

Uncommon: convulsions, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia)

Rare: dizziness during intravenous administration which in most cases can be prevented or resolved by extending the duration of the infusion.

Eye disorders

Rare: transient visual disturbances (e.g. blurred vision) particularly during intravenous administration

Very rare: transient blindness particularly during intravenous administration Most reported cases of blindness resolved within 20 minutes.

Most of the patients were being treated with chemotherapeutic agents including cisplatin. Some cases of transient blindness have been traced to a "cortical origin."

Cardiac pathologies

Uncommon: arrhythmias, chest pain with or without ST segment sublevel, bradycardia, Rare: QT prolongation (including Torsade de Pointes).

Vascular pathologies

Common: feeling hot or flushing

Uncommon: hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon: hiccups

Gastrointestinal disorders

Common: constipation, localized burning sensation following the use of suppositories

Hepatobiliary disorders

Uncommon: asymptomatic changes in liver function tests #

#These events were commonly seen in patients receiving cisplatin chemotherapy.

Skin and subcutaneous tissue disorders

Very rare: toxic skin rash, including toxic epidermal necrolysis.

General disorders and administration site conditions

Common: Local reactions at the intravenous injection site

Pediatric population

The adverse event profile in children and adolescents is comparable to that seen in adults. Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at "www.agenziafarmaco.gov.it/it/responsabili".

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

Expiry and Retention

Expiry: see the expiry date indicated on the package.

The expiry date refers to the product in intact packaging, correctly stored. Warning: do not use the medicine after the expiry date indicated on the package.

Validity after first opening or first withdrawal

ZOFRAN 4 mg / 2 ml Solution for injection and ZOFRAN 8 mg / 4 ml Solution for injection (Ampoules): the ampoules do not contain preservatives and must be used only once, injected or diluted immediately after opening: any remaining solution must be deleted.

ZOFRAN 40 mg / 20 ml Solution for injection (Multidose bottle): it has been shown that, after the first withdrawal, the product, protected from light, is chemically and physically stable for 28 days at 30 ° C. From a microbiological point of view, it is however advisable to store the product at 2-8 ° C, for a maximum of 28 days. Different storage conditions or longer storage times are the responsibility of the user.

Conservation rules

ZOFRAN 4 mg / 5 ml Syrup should not be kept in the refrigerator. Store the bottle upright.

ZOFRAN Solution for injection 4 mg / 2 ml and 8 mg / 4 ml (Ampoules) and 40 mg / 20 ml Solution for injection (Multidose bottle): must be stored at a temperature below 30 ° C and protected from light.

ZOFRAN 16 mg Suppositories: store below 30 ° C.

KEEP THIS MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

COMPOSITION

ZOFRAN 4 mg Film-coated tablets

one tablet contains: Active ingredient: ondansetron hydrochloride dihydrate 5 mg

equal to ondansetron 4 mg

Excipients: Anhydrous lactose, microcrystalline cellulose, pregelatinised maize starch, magnesium stearate, hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172).

ZOFRAN 8 mg Film-coated tablets

one tablet contains:

Active ingredient: ondansetron hydrochloride dihydrate 10 mg

equal to ondansetron 8 mg

Excipients: Anhydrous lactose, microcrystalline cellulose, pregelatinised maize starch, magnesium stearate, hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172).

ZOFRAN 4 mg Orodispersible tablets

one tablet contains:

Active ingredient: ondansetron 4 mg

Excipients: Gelatin, Mannitol, Aspartame, Sodium methyl parahydroxybenzoate, Sodium propyl parahydroxybenzoate, Strawberry flavor (contains ethanol *).

ZOFRAN 8 mg Orodispersible tablets

one tablet contains:

active ingredient: ondansetron 8 mg

Excipients: Gelatin, Mannitol, Aspartame, Sodium methyl parahydroxybenzoate, Sodium propyl parahydroxybenzoate, Strawberry flavor (contains ethanol).

ZOFRAN 4 mg / 5 ml Syrup

5 ml of syrup contains:

active ingredient: ondansetron hydrochloride dihydrate 5 mg equal to ondansetron 4 mg

Excipients: Anhydrous citric acid [E330], Sodium citrate dihydrate, Sodium benzoate [E211], Sorbitol solution [E420], Strawberry flavor (contains ethanol), Purified water.

ZOFRAN - 4 mg / 2 ml Solution for injection

one vial contains:

active ingredient: ondansetron hydrochloride dihydrate 5 mg equal to ondansetron 4 mg

Excipients: Citric acid monohydrate, Sodium citrate, Sodium chloride, Water for injections.

ZOFRAN - 8 mg / 4 ml Solution for injection

one vial contains:

active ingredient: ondansetron hydrochloride dihydrate 10 mg equal to ondansetron 8 mg

Excipients: Citric acid monohydrate, Sodium citrate, Sodium chloride, Water for injections.

ZOFRAN - 40 mg / 20 ml Solution for injection

1 ml of solution for injection contains:

active ingredient: ondansetron hydrochloride dihydrate 2.50 mg equal to ondansetron 2 mg

Excipients: Citric acid monohydrate, Sodium citrate, Sodium chloride, Methyl para-hydroxybenzoate, Propyl para-hydroxybenzoate, Water for injections.

ZOFRAN - 16 mg Suppositories

a suppository contains:

active ingredient: ondansetron 16 mg

Excipients: Mixture of mono-, di-, triglycerides of saturated fatty acids (Witepsol S58).

PHARMACEUTICAL FORM AND CONTENT

  • Film-coated tablets: 6 tablets of 4 mg
  • Film-coated tablets: 6 tablets of 8 mg
  • Orodispersible tablets: 6 tablets of 4 mg
  • Orodispersible tablets: 6 tablets of 8 mg
  • Syrup: 50 ml bottle
  • Solution for injection: 1 ampoule (4 mg / 2 ml)
  • Solution for injection: 1 ampoule (8 mg / 4 ml)
  • Solution for injection: 20 ml bottle (40 mg / 20 ml)
  • Suppositories: 4 suppositories of 16 mg

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Zofran can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ZOFRAN

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

ZOFRAN 4 mg Film-coated tablets

one tablet contains :

active ingredient: ondansetron hydrochloride dihydrate 5 mg

equal to ondansetron 4 mg.

Excipients with known effects: anhydrous lactose.

ZOFRAN 8 mg Film-coated tablets

one tablet contains :

active ingredient: ondansetron hydrochloride dihydrate 10 mg

equal to ondansetron 8 mg.

Excipients with known effects: anhydrous lactose.

ZOFRAN 4 mg Orodispersible tablets

one orodispersible tablet contains:

active ingredient: ondansetron 4 mg.

Excipients with known effects: aspartame, sodium methyl para-hydroxybenzoate, propyl para-hydroxybenzoate.

ZOFRAN 8 mg Orodispersible tablets

one orodispersible tablet contains:

active ingredient: ondansetron 8 mg.

Excipients with known effects: aspartame, sodium methyl para-hydroxybenzoate, propyl para-hydroxybenzoate.

ZOFRAN 4 mg / 2 ml Solution for injection

one vial contains:

active ingredient: ondansetron hydrochloride dihydrate 5 mg

equal to ondansetron 4 mg.

Excipients with known effects: sodium.

ZOFRAN 8 mg / 4 ml Solution for injection

one vial contains :

active ingredient: ondansetron hydrochloride dihydrate 10 mg

equal to ondansetron 8 mg.

Excipients with known effects: sodium.

ZOFRAN 40 mg / 20 ml Solution for injection

1 ml of solution for injection contains:

active ingredient: ondansetron hydrochloride dihydrate 2.5 mg

equal to ondansetron 2 mg.

Excipients with known effects: methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium.

ZOFRAN 4 mg / 5 ml Syrup

5 ml of syrup contain :

active ingredient: ondansetron hydrochloride dihydrate 5 mg

equal to ondansetron 4 mg.

Excipients with known effects: sorbitol, sodium.

ZOFRAN 16 mg Suppositories

1 suppository contains :

active ingredient: ondansetron 16 mg.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets.

Orodispersible tablets.

Syrup.

Solution for injection for intravenous and intramuscular use.

Suppositories.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Adults

Control of nausea and vomiting induced by antiblastic chemotherapy and radiotherapy; prophylaxis and treatment of post-operative nausea and vomiting (PONV).

Pediatric population:

Zofran is indicated for the control of chemotherapy induced nausea and vomiting (CINV) in children 6 months of age and older, and for the prevention and treatment of PONV in children 1 month and older.

04.2 Posology and method of administration

Nausea and vomiting induced by chemotherapy (CINV) and radiotherapy (RINV)

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The choice of dose regimen should be determined by the severity of the emesis.

ZOFRAN can be administered orally (Tablets / Orodispersible Tablets, Syrup), by intravenous or intramuscular injection, or rectally (Suppositories).

Populations

• CINV and RINV in adults:

Initial treatment

The usual dosage is 8 mg before chemotherapy or radiotherapy administered as follows:

- Solution for injection: 8 mg intravenously slowly (in not less than 30 seconds) or intramuscularly, immediately before treatment;

- Orodispersible Tablets / Tablets: 8 mg taken 1 or 2 hours before chemotherapy or radiotherapy treatment, followed by 8 mg orally every 12 hours for up to 5 days;

- Syrup: 10 ml (8 mg) 2 hours before treatment.

In cases of highly emetogenic chemotherapy, corticosteroid therapy may be associated.

Alternatively, a 16 mg suppository can be used to be administered 1-2 hours before treatment.

In some cases (use of highly emetizing cytotoxic drugs and / or prescribed at very high doses; presence of factors related to the patient, such as young, female subjects or with previous emetic phenomena during previous cytotoxic treatments) it is possible to use:

• A single 8 mg dose by slow intravenous injection (over not less than 30 seconds) or intramuscularly immediately prior to chemotherapy.

• One 8 mg dose by slow intravenous injection (over not less than 30 seconds) or intramuscular injection immediately before chemotherapy, followed by two further intravenous injections (over not less than 30 seconds) or intramuscular doses of 8 mg four hours apart one from the other, or with a constant infusion of 1mg / hour for up to 24 hours.

• a maximum starting dose of 16 mg diluted in 50-100 ml of sodium chloride 9 mg / ml (0.9%) solution for injection or other compatible infusion fluid (see section 6.6) and administered by infusion, for at least 15 minutes immediately before chemotherapy treatment).

The initial dose of Zofran can be followed by two further 8 mg intravenous doses (in no less than 30 seconds) or intramuscular doses 4 hours apart.

A single dose greater than 16 mg should not be administered due to the dose-dependent increased risk of QT interval prolongation (see sections 4.4, 4.8 and 5.1).

The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by the administration of a single 20 mg intravenous dose of dexamethasone sodium phosphate, administered prior to chemotherapy.

Continuation of therapy (prevention of delayed or prolonged emesis).

8 mg of ondansetron orally (tablets / orodispersible tablets, syrup) every 12 hours, or 1 suppository of 16 mg per day in the following days, for an average duration of 2 to 3 days, with the possibility of continuing up to 5 days.

Pediatric population:

CINV in children 6 months of age and older and adolescents

The dose for CINV can be calculated by body surface area (BSA) or by weight - see below. Weight calculation results in higher doses than body surface area calculation (see sections 4.4 and 5.1).

The ondansetron injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion solutions (see section 6.6) and administered intravenously over not less than 15 minutes.

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of postoperative nausea and vomiting; the intravenous formulation is recommended for this purpose.

There are no data from controlled clinical trials on the use of Zofran in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of Zofran in radiotherapy induced nausea and vomiting in children.

Dosage according to BSA:

Zofran should be administered immediately prior to chemotherapy as a single intravenous dose of 5 mg / m2. The single intravenous dose should not exceed 8 mg.

Oral administration can commence 12 hours later and can be continued for up to 5 days (table 1).

The total 24 hour dose (given in single doses) should not exceed the adult dose of 32 mg.

Table 1: Chemotherapy Dosage Based on BSA - Children aged ≥6 months and adolescents


BSA Day 1 (a, b) Days 2-6 (b) 2 5 mg / m2 i.v. and 2 mg syrup after 12 hours 2 mg syrup every 12 hours ≥0.6 m2 5 mg / m2 i.v. and 4 mg syrup or tablets after 12 hours 4 mg syrup or tablets every 12 hours

a The intravenous dose should not exceed 8 mg

b The total daily dose should not exceed adult dose of 32 mg

Dosage based on body weight:

Weight-based dosing results in a higher total daily dose compared to dosing for BSA (sections 4.4 and 5.1).

Zofran should be administered immediately prior to chemotherapy as a single intravenous dose of 0.15 mg / kg. The intravenous dose should not exceed 8 mg. Two further intravenous doses may be administered at 4-hour intervals.

The total dose in 24 hours should not exceed the adult dose of 32 mg.

Oral dosing can begin 12 hours later and can continue for up to 5 days (Table 2).

Table 2: Dosage for chemotherapy based on body weight - Children aged ≥6 months and adolescents


Body weight Day 1 (a, b) Days 2-6 (b) ≤10 kg Up to three doses of 0.15 mg / kg every 4 hours 2 mg syrup every 12 hours > 10 kg Up to three doses of 0.15 mg / kg every 4 hours 4 mg syrup or tablets every 12 hours

a The intravenous dose should not exceed 8 mg

b The total 24 hour dose should not exceed adult dose of 32 mg.

Zofran can be given as a single intravenous injection of 5 mg / m2, immediately prior to chemotherapy, followed by 4 mg orally (1 tablet / orodispersible tablets or 5 ml syrup) after 12 hours.

This regimen should be followed by oral therapy (tablets, orodispersible tablets or syrup) at a dosage of 4 mg (5 ml of syrup) twice a day, up to 5 days after the treatment cycle.

Suppositories

The use of ondansetron suppositories is not recommended in children. The usual route of administration is intravenous followed by oral therapy (see "Pediatric population" - oral formulations and solution for injection).

Elderly patients

In patients aged 65 to 74 years, the adult dosing schedule can be followed.

All intravenous doses should be diluted in 50 - 100 ml of saline or other compatible infusion fluids (see section 6.6) and infused over not less than 15 minutes.

In patients 75 years of age or older, the initial intravenous dose of Zofran should not exceed 8 mg.

All intravenous doses should be diluted in 50 - 100 ml of saline or other compatible infusion fluids (see section 6.6) and infused over not less than 15 minutes.

The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg each, infused over not less than 15 minutes and not less than 4 hours apart (see section 5.2).

Patients with renal insufficiency

No adjustment of dosage or frequency or route of administration is necessary.

Patients with hepatic insufficiency

In subjects with moderate or severe impairment of hepatic function, the clearance of ondansetron is significantly reduced and the serum half-life is significantly increased. In such patients the total daily dose of 8 mg should not be exceeded and therefore administration per day is recommended. orally or parenterally.

Post-operative nausea and vomiting (PONV)

The use in the indication post-operative nausea and vomiting is reserved for hospital use.

Zofran can be administered orally (Tablets / Orodispersible Tablets or Syrup) or by intravenous or intramuscular injection.

Adults

For the prophylaxis of post-operative nausea and vomiting, Zofran can be administered as a single 4 mg dose by intramuscular or slow intravenous injection upon induction of anesthesia or orally as a single dose of 16 mg (2 tablets, orodispersible tablets or 20 tablets). ml of syrup), one "hour before" anesthesia.

For the treatment of post-operative nausea and vomiting, when already established, a single dose of 4 mg administered by slow intramuscular or intravenous injection is recommended.

Pediatric population:

Prevention of post-operative nausea and vomiting (PONV) in children aged ≥1 month and adolescents

Injectable solution

For the prevention of PONV in pediatric patients undergoing surgery under general anesthesia, ondansetron can be administered as a single dose, by slow intravenous injection (over no less than 30 seconds), at a dose of 0.1 mg / kg up to a maximum dose of 4 mg either before, during or after induction of anesthesia, or after surgery.

For the treatment of PONV in pediatric patients undergoing surgery under general anesthesia, ondansetron can be administered as a single dose, by slow intravenous injection (over not less than 30 seconds), at a dose of 0.1 mg / kg up to a maximum dose of 4 mg.

There are no data on the use of ondansetron in the treatment of PONV in children less than 2 years of age.

Oral formulations

PONV in children aged ≥1 month and adolescents

No studies have been performed on the use of orally administered ondansetron in prophylaxis or in the treatment of post-operative nausea and vomiting: a slow intravenous injection is recommended for this purpose.

There are no data on the use of Zofran in the treatment of PONV in children less than 2 years of age.

Senior citizens

Experience with the use of Zofran in the prophylaxis and treatment of post-operative nausea and vomiting in the elderly is limited. However, Zofran is well tolerated in patients over 65 years of age receiving chemotherapy.

Patients with renal insufficiency

No adjustment of dosage or frequency or route of administration is necessary.

Patients with hepatic insufficiency

In subjects with moderate or severe impairment of hepatic function, the clearance of ondansetron is significantly reduced and the serum half-life is significantly increased. In such patients the total daily dose of 8 mg should not be exceeded and therefore administration per day is recommended. orally or parenterally.

Patients with insufficient metabolic oxidative capacities of Sparteine ​​/ Debrisoquine

The elimination half-life of ondansetron is not modified in subjects with insufficient metabolic oxidative capacities of Sparteine ​​/ Debrysoquine. Therefore in such patients repeated doses will result in drug exposure levels that do not differ from those of the general population. No changes are therefore required. the dosage or frequency of administration.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Based on reports documenting reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Pregnancy, lactation (see section 4.6).

Due to the presence of aspartame, Zofran Orodispersible tablets is contraindicated in patients with phenylketonuria.

04.4 Special warnings and appropriate precautions for use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists.

Reactions in the respiratory system must be treated with symptoms and doctors must pay particular attention to them as they can be precursors of hypersensitivity reactions.

Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, cases of Torsade de Pointes have been reported in patients treated with ondansetron during the post-marketing setting.

Avoid administration of ondansetron in patients with congenital long QT syndrome.

Ondansetron should be administered with caution to patients who have or may develop QTc prolongation. These conditions include patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmia, or patients taking other medications that lead to QT prolongation or electrolyte disturbance.

Therefore, caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic or beta-blocking agents, and in patients with significant electrolyte disturbances.

Hypokalaemia and hypomagnesaemia should be corrected prior to administration of ondansetron.

Cases of serotonin syndrome have been reported with the use of serotonin (5-HT3) antagonists, both alone but especially in combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs) and reuptake inhibitors serotonin-noradrenaline (SNRI)) It is recommended that patients be kept under adequate observation for any symptoms attributable to serotonin syndrome.

As ondansetron is known to increase the transit time of the large intestine, patients with symptoms of subacute intestinal obstruction given ondansetron should be monitored.

Prevention of nausea and vomiting with ondansetron may mask occult bleeding in patients who have undergone adenotonsillar surgery. Consequently, such patients should be followed closely after ondansetron administration.

Pediatric population:

Pediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be closely monitored for hepatic insufficiency.

Chemotherapy induced nausea and vomiting: When calculating the dose on an mg / kg basis and administering three doses at 4-hour intervals, the total daily dose will be higher than when administering a single dose of 5 mg / m2. The comparative efficacy of these two different dosing regimens has not been investigated in clinical studies. A cross-comparison indicates similar efficacy for both regimens (see section 5.1).

Important information about some of the excipients

Zofran Film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose / galactose malabsorption should not take this medicine.

ZOFRAN 4 mg orodispersible tablets contain small amounts of ethanol less than 100 mg per dose (may contain up to 0.0015 mg of ethanol) and ZOFRAN 8 mg orodispersible tablets contain small amounts of ethanol less than 100 mg per dose (may contain up to 0.003 mg of ethanol).

Zofran orodispersible tablets contain aspartame, a source of phenylalanine. They can be harmful if you have phenylketonuria.

Zofran orodispersible tablets contain methyl parahydroxybenzoate and propyl parahydroxybenzoate. It can cause allergic reactions (even delayed).

Zofran 40 mg / 20 ml solution for injection contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. It can cause allergic reactions (even delayed) and, exceptionally, bronchospasm.

Zofran 40 mg / 20 ml solution for injection contains sodium (0.25 mg / ml as sodium citrate and 8.30 mg / ml as sodium chloride) To be taken into consideration by people on a low sodium diet.

Zofran syrup contains sorbitol. Patients with rare hereditary problems with fructose should not take this medicine.

Zofran syrup contains sodium (7.5 mg as sodium citrate and 10 mg as sodium benzoate). To be taken into consideration in people on a low sodium diet.

Zofran syrup contains contains small amounts of ethanol (3 mg in 5 ml of syrup).

04.5 Interactions with other medicinal products and other forms of interaction

There is no evidence that ondansetron induces or inhibits the metabolism of other drugs usually administered concurrently.

Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolizing ondansetron, enzyme inhibition or reduced activity of one enzyme (eg genetic deficiency of CYP2D6) is generally compensated by other enzymes and the total clearance of ondansetron or the required dosage must undergo slight or insignificant changes.

Caution is required when ondansetron is administered in combination with drugs that prolong the QT interval and / or cause electrolyte abnormalities (see section 4.4).

Use of Zofran with drugs that prolong the QT interval may result in further prolongation. Concomitant use of Zofran with cardiotoxic drugs (anthracyclines such as doxorubicin and daunorubicin, or trastuzumab), antibiotics (such as erythromycin), ketoconazole, antiarrhythmics (such as amiodarone) and beta-blockers (such as atenolol or timolol) may increase the risk arrhythmias (see section 4.4).

Apomorphine

Based on reports documenting reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Phenytoin, carbamazepine and rifampicin

In patients treated with potent CYP3A4 inducers (e.g. phenytoin, carbamazepine and rifampicin) the oral clearance of ondansetron was increased and ondansetron plasma concentrations decreased.

Serotonergic drugs (for example: SSRIs and SNRIs)

Cases of serotonin syndrome have been reported following the concomitant use of serotonin (5-HT3) antagonists and other serotonergic drugs (including SSRIs and SNRIs).

Tramadol

Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

04.6 Pregnancy and breastfeeding

Pregnancy

The safety of ondansetron in human pregnancy has not been established.

Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to embryo-fetal development, gestation and peri- and postnatal development.

However, as animal studies are not always predictive of human response, ondansetron should not be administered during pregnancy.

Feeding time

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers being treated with ondansetron do not breastfeed.

04.7 Effects on ability to drive and use machines

In psychomotor tests, ondansetron does not alter performance or cause sedation. Based on the pharmacology of ondansetron, no harmful effects on these activities are expected.

04.8 Undesirable effects

Side effects are listed below by organ, system / system and by frequency. Frequencies are defined as: very common (≥1 / 10), common (≥1 / 100 and

The following frequencies are estimated based on the standard recommended doses of ondansetron, depending on the indication and formulation.

Disorders of the immune system

Rare: immediate hypersensitivity reactions, sometimes severe, including anaphylactic reactions.

Nervous system disorders

Very common: headache

Uncommon: convulsions, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia).

Rare: dizziness during intravenous administration which in most cases can be prevented or resolved by extending the duration of the infusion.

Eye disorders

Rare: transient visual disturbances (e.g. blurred vision) particularly during intravenous administration

Very rare: transient blindness particularly during intravenous administration.

Most of the reported cases of blindness resolved within 20 minutes. Most of the patients were being treated with chemotherapeutic agents including cisplatin. Some cases of transient blindness have been traced to a "cortical origin."

Cardiac pathologies

Uncommon: arrhythmias, chest pain with or without ST segment sub-leveling, bradycardia

Rare: QTc interval prolongation (including Torsade de Pointes).

Vascular pathologies

Common: feeling hot or flushing.

Uncommon: hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: hiccups.

Gastrointestinal disorders

Common: constipation.

Localized burning sensation following the use of suppositories.

Hepatobiliary disorders

Uncommon: asymptomatic changes in liver function tests #.

#These events were commonly seen in patients receiving cisplatin chemotherapy.

Skin and subcutaneous tissue disorders

Very rare: toxic skin rash, including toxic epidermal necrolysis.

General disorders and administration site conditions

Common: Local reactions at the intravenous injection site.

Pediatric population

The adverse event profile in children and adolescents is comparable to that seen in adults.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

Signs and symptoms

There is limited experience of overdose with ondansetron. In most cases, symptoms were similar to those already reported in patients administered the recommended doses (see section 4.8).

Manifestations that have been reported include visual disturbances, severe constipation, hypotension, and a vasovagal episode with transient and second-degree atrioventricular block.

Ondansetron prolongs the QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.

Treatment

There is no specific antidote for ondansetron; therefore, in cases of suspected overdose, appropriate symptomatic and supportive therapy should be administered.

The use of ipecac for the treatment of ondansetron overdose is not recommended as patient response is unlikely due to the antiemetic action of ondansetron itself.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiemetics and antinauseants - serotonin (5HT3) antagonists.

ATC code: A04AA01.

Mechanism of action

Ondansetron is a highly selective 5HT3 receptor antagonist with high potency. Its mechanism of action, in the control of nausea and vomiting, is not yet well known; however, it is known that chemotherapeutic agents and radiotherapy can cause a release of serotonin from the small intestine which in turn, through vagal afferents via 5HT3 receptors, can trigger the gag reflex; ondansetron is able to inhibit this reflex.

Furthermore, the activation of the vagal afferent pathways can determine, at the level of the postrema area, located on the floor of the IV ventricle, the release of serotonin and this can stimulate vomiting through a central mechanism.

The efficacy of ondansetron in controlling the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to its antagonistic action on the 5HT3 receptors of neurons located both in the Central and Peripheral Nervous System.

Oral and injectable formulations

The mechanism of action in the control of post-operative nausea and vomiting is not known but is expected to be similar to the control mechanism of cytotoxic induced nausea and vomiting.

Pharmacodynamic effects

Ondansetron does not interfere with plasma prolactin levels.

Prolongation of the QT interval

The effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo- and active-drug (moxifloxacin) controlled crossover study in 58 healthy adult men and women. The doses of ondansetron included were 8 and 32 mg infused intravenously over at least 15 minutes. At the highest tested dose of 32 mg, the maximum mean difference (upper limit of 90% CI) in the QTcF interval from placebo after baseline correction was 19.6 (21.5) milliseconds. At the lowest tested dose of 8 mg, the maximum mean difference (upper limit of 90% CI) in QTcF from placebo after baseline correction was 5.8 (7.8) milliseconds. In this study, there were no measurements. of QTcF greater than 480 milliseconds and there were no QTcF prolongations greater than 60 milliseconds No significant changes were observed in the electrocardiographically measured PR and QRS intervals.

Pediatric population

CINV

The efficacy of ondansetron in the control of chemotherapy-induced vomiting and nausea was documented in a randomized double-blind study of 415 patients aged 1 to 18 years (S3AB3006). During the days of chemotherapy, patients received ondansetron 5 mg / m2 intravenously + ondansetron 4 mg orally after 8-12 hours or ondansetron 0.45 mg / kg intravenously + placebo orally after 8-12 hours. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Overall, there was no difference in the incidence or nature of adverse events between the two treatment groups. Complete control of vomiting on the worst day of chemotherapy was 49% (intravenous 5 mg / m2 + oral ondansetron 4 mg) and 41% (intravenous 0.45 mg / kg + oral placebo). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.

A randomized double-blind placebo-controlled study (S3AB4003) in 438 patients aged 1-17 years demonstrated complete control of vomiting on the worst day of chemotherapy on:

• 73% of patients when ondansetron was administered intravenously at a dose of 5 mg / m2 with dexamethasone 2-4 mg orally.

• 71% of patients when ondansetron was administered as a syrup at a dose of 8 mg + 2-4 mg dexamethasone orally on chemotherapy days.

Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for two days. Overall, there was no difference in the incidence or nature of adverse events between the two treatment groups.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, non-comparative, one-arm study (S3A40320). All children received three doses of 0.15 mg / kg. intravenous ondansetron administered 30 minutes before the start of chemotherapy and then at the fourth and eighth hours after the first dose. Complete control of vomiting was achieved in 56% of patients.

Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of an intravenous dose of 0.15 mg / kg of ondansetron followed by two oral doses of 4 mg ondansetron for children aged

PONV

The efficacy of a single dose of ondansetron in the prevention of postoperative nausea and vomiting was investigated in a randomized, double-blind, placebo-controlled study in 670 infants aged 1 to 24 months (post-conception age). ≥ 44 weeks, weight ≥3 kg). Recruited subjects were slated to undergo elective surgery under general anesthesia and achieved ASA status ≤III. A single dose of ondansetron 0.1 mg / kg was administered within five minutes after induction of anesthesia. The proportion of subjects who had at least one episode of vomiting during the 24-hour evaluation period (ITT) was higher for patients in the placebo group than for those on ondansetron (28% vs 11%, p

Four double-blind, placebo-controlled studies were conducted in 1,469 male and female patients (aged 2 to 12 years) undergoing general anesthesia. Patients were randomized to receive either single intravenous doses of ondansetron (0.1 mg / kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg; number of patients = 735) or placebo (number of patients = 734). Study drug was administered for at least 30 seconds, immediately prior to induction of anesthesia or immediately thereafter. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarized in Table 3.

Table 3 Prevention and Treatment of PONV in Pediatric Patients - 24 Hour Response to Treatment


Study Endpoint % of Ondansetron % of Placebo Value of p S3A380 CR 68 39 ≤0.001 S3GT09 CR 61 35 ≤0.001 S3A381 CR 53 17 ≤0.001 S3GT11 no nausea 64 51 0.004 S3GT11 no vomiting 60 47 0.004

CR = no episodes of emesis, rescue or study withdrawal.

05.2 Pharmacokinetic properties

The pharmacokinetic characteristics of ondansetron are not affected by the administration of repeated doses.

Absorption

Oral formulations

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations are reached approximately 1.5 hours after administration. For doses above 8 mg the increase in systemic exposure to ondansetron is more than proportional; this may be due to some degree of reduction in first pass metabolism at higher oral doses.

Bioavailability is slightly increased by the presence of food but is not modified by antacids.

Injectable solution

Following administration of ondansetron i.m. and e.v. an equivalent systemic exposure is obtained.

Suppositories

After administration of ondansetron in suppositories, plasma concentrations of ondansetron are detected 15-60 minutes after treatment.

The increase in concentrations occurs in a substantially linear fashion up to peak concentrations of 20-30 ng / ml, usually 6 hours after administration. Thereafter, plasma concentrations decrease, but at a slower rate than that observed after oral administration. this as a consequence of the prolonged absorption of ondansetron.

The bioavailability of ondansetron after administration as suppositories is approximately 60%.

Distribution

Ondansetron binds to plasma proteins in a variable percentage between 70 and 76%.

Oral formulations and solution for injection

The distribution and elimination of ondansetron measured in adults following oral, i.m. or i.v. administration is similar, with a steady-state volume of distribution of approximately 140 liters.

Metabolism

Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism via multiple enzyme pathways. The absence of the CYP2D6 enzyme (debrisoquine polymorphism) has no effect on the pharmacokinetics of ondansetron.

Elimination

Ondansetron is eliminated from the systemic circulation predominantly by hepatic metabolism. Less than 5% of the absorbed dose is excreted unchanged in the urine.

Oral formulations and solution for injection

Distribution of ondansetron following oral administration, i.m. or i.v. it is similar, with an elimination half-life of approximately 3 hours.

Suppositories

The half-life of the elimination phase is determined by the absorption rate of ondansetron, not systemic clearance and is approximately 6 hours.

Special patient populations

Sex

Oral formulations and solution for injection

Gender differences in the availability of ondansetron were noted: women have a higher degree and rate of absorption following oral administration and reduced systemic clearance and volume of distribution (adjusted for body weight).

Suppositories

Absolute bioavailability is not affected by gender. A small increase in the half-life is observed in women compared to men, which is not clinically significant.

Children and adolescents (aged 1 month to 17 years)

Oral formulations and solution for injection

In pediatric patients aged 1 to 4 months (n = 19) undergoing surgery, clearance normalized to body weight was approximately 30% slower than that in patients aged 5 to 24 months (n = 22) but comparable to that of patients aged between 3 and 12 years. The half-life in the patient population aged 1 to 4 months was reported with a mean value of 6.7 hours compared to 2.9 hours for patients in the age range of 5 to 24 months and between 3 and 12 years old. Differences in pharmacokinetic parameters in the patient population aged 1 to 4 months can be explained in part by the higher percentage of total body water in neonates and infants and the higher volume of distribution for water-soluble drugs such as ondansentron. .

In pediatric patients aged 3 to 12 years undergoing surgery under general anesthesia, the absolute values ​​of both the clearance and volume of distribution of ondansetron were reduced compared to the values ​​in adult patients. Both parameters increased linearly with weight and from 12 years of age onwards the values ​​approached those of young adults. When clearance and volume of distribution values ​​were normalized by body weight, the values ​​of these parameters were similar across populations at different age groupings. The use of a weight-aware dosing technique compensates for age-related changes and is effective in normalizing systemic exposure in pediatric patients.

Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgical patients and healthy volunteers) aged 1 month to 44 years after intravenous administration of ondansetron. Based on this analysis, systemic exposure ( AUC) of ondansetron following an oral or intravenous dose in children and adolescents was comparable to adults, with the exception of children aged 1 to 4 months. The volume was age-related and was lower in adults than in adults. to babies and children. Clearance was related to weight but not age with the exception of infants 1 to 4 months of age. It is difficult to conclude that there was a further reduction in age-related clearance in infants from 1 to 4 months or simply inherent in the variability due to the small number of subjects studied in this age group. 6 months will receive only a single dose in PONV a reduced clearance is not likely to be clinically relevant.

Senior citizens

Early phase I studies in healthy elderly volunteers have shown a slight increase in oral bioavailability and a prolongation of the elimination half-life, related to age.

However, the large inter-subject variability resulted in considerable overlap in pharmacokinetic parameters among young people (

Suppositories

Specific studies in the elderly or in patients with renal insufficiency have been limited to the intravenous and oral routes of administration.

Nevertheless, it can be assumed that the half-life of ondansetron in elderly patients is similar to that observed in healthy volunteers as the degree of elimination of ondansetron following administration of suppositories is not determined by systemic clearance.

Kidney failure

In patients with moderate renal insufficiency (creatinine clearance 15 to 60 ml / min) both systemic clearance and volume of distribution are reduced following intravenous administration of ondansetron, resulting in a slight, but clinically insignificant, increase in the half-life. of elimination (5, 4 hours).

A study in patients with severe renal insufficiency undergoing regular hemodialysis showed that the pharmacokinetics of ondansetron, detected in the interdialytic periods, were substantially unchanged following IV administration.

Suppositories

Specific studies in patients with renal insufficiency have been limited to the intravenous and oral routes of administration.

Nevertheless, it can be assumed that the half-life of ondansetron in patients with renal insufficiency is similar to that observed in healthy volunteers as the degree of elimination of ondansetron following administration of suppositories is not determined by systemic clearance.

Hepatic insufficiency

Oral formulations and solution for injection

In patients with severe hepatic impairment, the systemic clearance of ondansetron is markedly reduced, the elimination half-life is prolonged (15-32 hours) and oral bioavailability approaches 100% due to reduced pre-systemic metabolism.

Suppositories

The pharmacokinetics of ondansetron following administration as suppositories have not been evaluated in patients with hepatic insufficiency.

05.3 Preclinical safety data

Oral formulations and suppositories

No additional relevant data.

Injectable solution

A study in cloned ion channels from the human heart has shown that ondansetron has the potential to affect cardiac repolarization by blocking HERG potassium channels. The clinical impact of this finding is unknown.

In vivo, QT interval prolongation was observed in anesthetized cats after intravenous administration, but at doses 100 times higher than pharmacologically effective. Similar effects were not observed in cynomolgus monkeys. Transient ECG changes have been reported in practice. clinic (see section 4.4).

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

ZOFRAN 4 mg Film-coated tablets and ZOFRAN 8 mg Film-coated tablets: Anhydrous lactose, microcrystalline cellulose, pregelatinised maize starch, magnesium stearate, hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172).

ZOFRAN 4 mg Orodispersible tablets and ZOFRAN 8 mg Orodispersible tablets: gelatin, mannitol, sodium aspartamemethyl para-hydroxybenzoate, sodium propyl para-hydroxybenzoate, strawberry flavor (Contains ethanol).

ZOFRAN 4 mg / 5 ml Syrup: anhydrous citric acid [E330], sodium citrate dihydrate, sodium benzoate [E211], sorbitol solution [E420], strawberry flavor (contains ethanol), purified water.

ZOFRAN 4 mg / 2 ml Solution for injection and ZOFRAN 8 mg / 4 ml Solution for injection: citric acid monohydrate, sodium citrate, sodium chloride, water for injections

ZOFRAN 40 mg / 20 ml Solution for injection: citric acid monohydrate, sodium citrate, sodium chloride, methyl para-hydroxybenzoate, propyl para-hydroxybenzoate, water for injections

ZOFRAN 16 mg Suppositories: mixture of mono-, di-, triglycerides of saturated fatty acids (Witepsol S58).

06.2 Incompatibility

Oral formulations and suppositories

None.

Injectable solution

Unlike other medicinal products, ondansetron for injection should not be administered in the same syringe or infusion fluid with other active substances (see section 6.6). Ondansetron for injection should only be administered in the recommended infusion solutions (see paragraph 6.6).

06.3 Period of validity

Period of validity

ZOFRAN 4 mg Film-coated tablets, ZOFRAN 8 mg Film-coated tablets, ZOFRAN 4 mg / 2 ml Solution for injection, ZOFRAN 40 mg / 20 ml Solution for injection,

ZOFRAN 8 mg / 4 ml Solution for injection, ZOFRAN 4 mg / 5 ml Syrup, ZOFRAN 16 mg

Suppositories: 3 years.

ZOFRAN 4 mg Orodispersible tablets, ZOFRAN 8 mg Orodispersible tablets: 3 years.

Validity after first opening or first withdrawal

ZOFRAN Solution for injection 4 mg / 2 ml and 8 mg / 4 ml (ampoules): the ampoules do not contain preservatives and must be used only once, injected or diluted immediately after opening: any remaining solution must be discarded.

ZOFRAN 40 mg / 20 ml Solution for injection (Multidose bottle): it has been shown that, after the first withdrawal, the product, protected from light, is chemically and physically stable for 28

days at 30 ° C. From a microbiological point of view, it is however advisable to store the product at 2 - 8 ° C for a maximum of 28 days. Different storage conditions or longer storage times are the responsibility of the user.

06.4 Special precautions for storage

ZOFRAN 4 mg / 5 ml Syrup should not be kept in the refrigerator. Store the bottle upright.

ZOFRAN Solution for injection 4 mg / 2 ml and 8 mg / 4 ml (ampoules) and 40 mg / 20 ml Solution for injection (Multidose bottle): must be stored at a temperature below 30 ° C and protected from light.

ZOFRAN suppositories: store below 30 ° C.

06.5 Nature of the immediate packaging and contents of the package

ZOFRAN 4 mg film-coated tablets, ZOFRAN 8 mg film-coated tablets:

aluminum / PVC / OPA blister; packages:

6 tablets of 4 mg

6 tablets of 8 mg

ZOFRAN 4 mg Orodispersible tablets, ZOFRAN 8 mg Orodispersible tablets: aluminum - aluminum blister; packages:

6 tablets of 4 mg

10 tablets of 4 mg

6 tablets of 8 mg

10 tablets of 8 mg

ZOFRAN 4 mg / 5 ml Syrup: Type III Ph. Eur. Amber glass bottle with child resistant closure, containing 50 ml of syrup, having an ondansetron concentration equal to 4 mg / 5 ml

ZOFRAN 4 mg / 2 ml Solution for injection, ZOFRAN 8 mg / 4 ml Solution for injection: type I colorless glass ampoules; packages:

1 ampoule of 4 mg

1 ampoule of 8 mg

2 ampoules of 4 mg

2 ampoules of 8 mg

ZOFRAN 40 mg / 20 ml Solution for injection: multidose bottle of colorless type I glass; 1 multidose bottle containing 20 ml of a 2 mg / ml solution of ondansetron

ZOFRAN 16 mg Suppositories: the suppositories are contained in a laminate of low density polyethylene / aluminum / propylene; pack of 4 suppositories in a cardboard box.

06.6 Instructions for use and handling

ZOFRAN 4 mg Orodispersible tablets and ZOFRAN 8 mg Orodispersible tablets.

Do not extract the tablets by pressing through the laminate.

Peel off the backing foil of a blister and gently remove the tablet.

Place the tablet on the tip of the tongue, where it will dissolve in a few moments, then swallow.

ZOFRAN 4 mg / 2 ml Injection Solution and ZOFRAN 8 mg / 4 ml Injection Solution (packed in ampoules, free of preservatives)

ZOFRAN Solution for injection must not be subjected to autoclaving.

Compatibility with infusion solutions

In accordance with the rules of good pharmaceutical practice, the intravenous solutions must be prepared at the time of infusion.

However, the preservative-free ondansetron solution for injection has been shown to be stable for 7 days at room temperature (below 25 ° C) under fluorescent light or in the refrigerator with the following infusion solutions:

- Sodium chloride for intravenous infusion 0.9% w / v

- Glucose solution for intravenous infusion 5% w / v

- Mannitol for intravenous infusion 10% w / v

- Ringer's solution for intravenous infusion

- Potassium chloride 0.3% w / v and sodium chloride 0.9% w / v for intravenous infusion

- Potassium chloride 0.3% w / v and glucose 5% w / v for intravenous infusion

Compatibility studies were performed using PVC infusion bags and sets.

It is believed that an "adequate stability of" ondansetron is possible using also polyethylene infusion bags or type I glass bottles.

The solution for injection without preservatives diluted in 0.9% w / v physiological solution or in 5% w / v glucose solution has been shown to be stable even in polypropylene syringes.

It is therefore believed that the ondansetron injectable solution with or without preservatives, diluted with the compatible infusion solutions indicated below, is also stable in polypropylene syringes.

Note: Preparations must be prepared under aseptic conditions if extended storage periods are required.

Compatibility with other drugs

Ondansetron can be administered by venous infusion at a dosage of 1 mg / hour eg with an infusion bag or with a plunger pump.

Administration of the following drugs is compatible with ondansetron at concentrations from 16 to 160 mcg / ml (e.g. 8 mg in 500 ml and 8 mg in 50 ml respectively) using a Y set:

Cisplatin: concentrations up to 0.48 mg / ml (eg 240 mg in 500 ml) administered over a period ranging from 1 to 8 hours.

5-Fluorouracil: concentrations up to 0.8 mg / ml (e.g. 2.4 g in 3 liters or 400 mg in 500 ml) administered at a rate of at least 20 ml per hour (500 ml for 24 hours).

Higher concentrations of 5-Fluorouracil can cause the precipitation of ondansetron. The 5-Fluorouracil infusion solution may contain up to 0.045% w / v of magnesium chloride in addition to the other excipients which have been shown to be compatible.

Carboplatin: concentrations ranging from 0.18 mg / mL to 9.9 mg / mL (e.g. 90 mg in 500 mL up to 990 mg in 100 mL) can be administered over a period ranging from 10 minutes to 1 hour.

Etoposide: concentrations ranging from 0.144 mg / ml to 0.25 mg / ml (eg 72 mg in 500 ml up to 250 mg in 1 liter) can be administered in a time varying between 30 min. and 1 hour.

Ceftazidime: dosages ranging from 250 mg to 2000 mg reconstituted with water p.p.i., as recommended by the manufacturer (2.5 ml for 250 mg and 10 ml for 2 g of ceftazidime), can be administered as an intravenous bolus in approximately 5 minutes.

Cyclophosphamide: dosages between 100 mg and 1 g, reconstituted with water p.p.i., 5 ml per 100 mg of cyclophosphamide, as recommended by the manufacturer, can be administered as an intravenous bolus over approximately 5 minutes.

Doxorubicin: dosages between 10 and 100 mg, reconstituted with water p.p.i., 5 ml per 10 mg of doxorubicin, as recommended by the manufacturer, can be administered as an intravenous bolus over approximately 5 minutes.

Dexamethasone: 20 mg of dexamethasone sodium phosphate can be administered by slow intravenous injection over 2-5 minutes using a Y infusion set that releases 8 to 16 mg ondansetron over approximately 15 minutes, diluted in 50-100 ml of a compatible infusion fluid. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated by allowing the administration of these drugs through the same set at concentrations from 32 mcg / ml to 2.5 mg / ml for dexamethasone sodium phosphate and from 8 mcg to 1 mg / ml for l "ondansetron.

ZOFRAN 40 mg / 20 ml Solution for Injection (Multidose bottle, with preservatives)

Compatibility studies were performed using PVC infusion bags and sets.

It is believed that an "adequate stability of" ondansetron is possible using also polyethylene infusion bags or type I glass bottles.

The solution for injection without preservatives diluted in 0.9% w / v physiological solution or in 5% w / v glucose solution has been shown to be stable even in polypropylene syringes.

It is therefore believed that the ondansetron injectable solution with or without preservatives, diluted with the compatible infusion solutions indicated below, is also stable in polypropylene syringes.

Note: Preparations must be prepared under aseptic conditions if extended storage periods are required.

Compatibility with infusion solutions

In accordance with the rules of good pharmaceutical practice, the intravenous solutions must be prepared at the time of infusion.

However, the ondansetron solution for injection with preservatives has been shown to be stable for 48 hours at room temperature (below 25 ° C) with the following infusion solutions:

- Sodium chloride for intravenous infusion 0.9% w / v

- Sodium chloride for intravenous infusion 3% w / v

- Glucose solution for intravenous infusion 5% w / v

- Sodium chloride 0.9% w / v and glucose solution for intravenous infusion 5% w / v

- Sodium chloride 0.45% w / v and glucose solution for intravenous infusion 5% w / v

In line with the medicinal product packaged in ampoules (without preservatives - see above) it is believed that adequate stability is maintained even with the following infusion solutions, although compatibility studies with these solutions have not been performed:

- Mannitol for intravenous infusion 10% w / v

- Ringer's solution for intravenous infusion

- Potassium chloride 0.3% w / v and sodium chloride 0.9% w / v for intravenous infusion

- Potassium chloride 0.3% w / v and glucose 5% w / v for intravenous infusion.

Compatibility with other drugs

Ondansetron, diluted with a compatible infusion solution, can be administered by venous infusion at a dosage of 1 mg / hour, e.g. with an infusion bag or plunger pump.

The following drugs can be co-administered, using a Y-set:

Cisplatin: concentrations up to 0.5 mg / ml (e.g. 250 mg in 500 ml) administered over a period ranging from 1 to 8 hours using a Y infusion set that releases ondansetron concentrations from 3 to 150 mcg / ml (e.g. 1.5 mg / 500 ml and 7.5 mg / 50 ml respectively).

Dexamethasone sodium phosphate: 20 mg administered by slow intravenous injection over 2-5 minutes using a Y-set that releases 8 to 16 mg ondansetron over approximately 15 minutes, diluted in 50-100 ml of a compatible infusion fluid.

ZOFRAN 4 mg / 2 ml Solution for injection and ZOFRAN 8 mg / 4 ml Solution for injection

Instructions for opening the vial.

The vials are equipped with a safety pre-opening and must be opened as follows:

- hold the lower part of the vial with one hand;

- place the other hand on the upper part, placing the thumb over the COLORED DOT and exert pressure.

07.0 MARKETING AUTHORIZATION HOLDER

GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - Verona.

08.0 MARKETING AUTHORIZATION NUMBER

ZOFRAN 4 mg Film-coated tablets: 6 tablets A.I.C .: 027612011

ZOFRAN 8 mg Film-coated tablets: 6 tablets A.I.C .: 027612023

ZOFRAN 4 mg Orodispersible tablets: 6 tablets A.I.C .: 027612098

ZOFRAN 8 mg Orodispersible tablets: 6 tablets A.I.C .: 027612112

ZOFRAN 4 mg / 5 ml Syrup: 50 ml bottle A.I.C .: 027612086

ZOFRAN 4 mg / 2 ml Solution for injection: pack of 1 ampoule of 2 ml A.I.C .: 027612035

ZOFRAN 8 mg / 4 ml Solution for injection: pack of 1 ampoule of 4 ml A.I.C .: 027612047

ZOFRAN 40 mg / 20 ml Solution for injection: bottle of 20 ml A.I.C .: 027612136

ZOFRAN 16 mg Suppositories: pack of 4 suppositories A.I.C .: 027612074

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Solution for injection, Film-coated tablets: 2 May 1991 / October 2008

Syrup: 12 January 1998 / October 2008

Suppositories: March 31, 1998 / October 2008

Orodispersible tablets: 13 December 1999 / October 2008

40 mg / 20 ml Solution for injection: 9 June 2000 / October 2008

10.0 DATE OF REVISION OF THE TEXT

February 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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