Components:
Method of action:
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Medically reviewed by Militian Inessa Mesropovna, PharmD. Last updated on 19.03.2022
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Isotolol 10% Solution for infusion is indicated for use as an osmotic diuretic in the following situations:
- Promotion of diuresis in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established.
- Reduction of intracranial pressure and cerebral oedema, when blood-barrier is intact.
- Reduction of elevated intraocular pressure when it cannot be lowered by other means.
- Promotion of elimination of renally excreted toxic substances in poisoning.
Isotol is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.
Posology:
The choice of the specific Isotolol concentration, dosage and rate of administration depends on the age, weight, clinical and biological condition of the patient and concomitant therapy.
Adults and adolescents:
Acute renal failure
The general dose range is 50 to 200 g Isotolol (500 ml to 2000 ml/day) in a 24 hour period, with a dosage limit of 50 g (500ml Isotolol) on any one occasion. In most instances, adequate response will be achieved at a dosage of 50 to 100 g Isotolol/day (500 ml to 1000 ml /day).
The rate of administration is usually adjusted to maintain a urine flow of at least 30-50 ml/hour.
Only in emergency situations, the maximum infusion rate can be as high as 200 mg/kg infused over 5 minutes (see also test dose). After 5 minutes, the infusion rate should be readjusted to maintain a urine flow of at least 30-50 ml/hour, with a maximal dose of 200 g/24h.
Use in patients with oliguria or renal impairment
Patients with marked oliguria or suspected inadequate renal function should first receive a test dose of approximately 200 mg Isotolol/kg bw (body weight) (2ml/kg bw) over a period of 3 to 5 minutes. For example: in an adult patient with a body weight of 70 kg: approximately 75 ml of a 20% solution or 100 ml of a 15% solution. The response to the test dose is considered adequate if at least 30-50 ml/hour of urine is excreted for 2-3 hours. If an adequate response is not attained, a further test dose may be given. If an adequate response to the second test dose is not attained, treatment with Isotolol should be discontinued and the patient reassessed as established renal failure may be present.
Reduction of intracranial pressure, cerebral volume and intraocular pressure
The usual dose is 1.5 to 2g/kg bw (15 to 20 ml/kg bw), infused over 30 to 60 minutes. When used preoperatively, the dose should be administered 1 to 1.5 hours before surgery to obtain the maximum effect.
Promotion of elimination of renally excreted toxic substances in poisoning
In forced diuresis, the dose of Isotolol should be adjusted to maintain urinary output of at least 100ml/hour and positive fluid balance of 1-2 litres. An initial loading dose of approximately 25 g (250 ml) may be given.
Paediatric population:
In renal insufficiency, the test dose should be 200 mg Isotolol/kg bw (2 ml/kg bw) over 3-5 minutes. The treatment dose ranges from 0.5 to 1.5 g/kg bw (5 ml/kg bw to 15 ml/kg bw). This dose may be repeated once or twice, after an interval of 4 to 8 hours, if necessary.
For cerebral and ocular oedema, this dose may be given over 30 to 60 minutes as for adults.
Elderly population:
As for adults, the dosage depends on the weight, clinical and biological condition of the patient and concomitant therapy. The general dose range is the same as for adults, 50 to 200 g in a 24 hour period (500 ml to 2000ml/day), with a dosage limit of 50 g Isotolol (500 ml) on any one occasion. Since incipient renal insufficiency may be present, caution should be used when reviewing patient's status prior to dose selection.
Method of administration:
The solution is for intravenous administration through sterile and non-pyrogenic equipment.
Hyperosmolar Isotolol solutions may cause vein damage. Check product's osmolarity before administration.
Use administration set which includes a final in-line filter because of the potential for Isotolol crystals to form and using an aseptic technique. The equipment should be primed with the solution in order to prevent air entering the system.
Do not remove unit from overwrap until ready for use. The inner bag maintains the sterility of the product.
Use only if the solution is clear, without visible particles or discoloration and the seal is intact. Confirm the integrity of the bag. Use only if the container is undamaged. Administer immediately following insertion of the infusion set.
This hypertonic solution should be administered via a large peripheral or preferably a central vein. Rapid infusion in peripheral veins may be harmful.
Isotolol solutions may crystallize when exposed to low temperature.6.
<6.The patient's initiation dose of Isotol must be used under the supervision and monitoring of an experienced physician or another health care professional appropriately trained and equipped to perform spirometry, monitor oxygen saturation (SpO2), and manage acute bronchospasm including appropriate use of resuscitation equipment.
Posology
Initiation dose assessment
Before commencing treatment with Isotol, all patients should be assessed for bronchial hyperresponsiveness to inhaled mannitol during administration of their initiation dose.
The patient should be pre-medicated with a bronchodilator 5-15 minutes prior to the initiation dose but after the baseline FEV1 and SpO2 (Oxygen saturation in the blood) measurement. All FEV1 measurements and SpO2 monitoring should be performed 60 seconds after dose inhalation.
Training the patient to practice correct inhaler technique during the initiation dose assessment is important.
The initiation dose assessment must be performed according to the following steps:
Step 1: Patients baseline FEV1 and SpO2 is measured prior to the initiation dose
Step 2: Patient inhales 40 mg (1x40 mg capsules) and SpO2 is monitored
Step 3: Patient inhales 80 mg (2x40 mg capsules) and SpO2 is monitored
Step 4: Patient inhales 120 mg (3x40 mg capsules), FEV1 is measured and SpO2 is monitored
Step 5: Patient inhales 160 mg (4x40 mg capsules), FEV1 is measured and SpO2 is monitored
Step 6: Patients FEV1 is measured 15 minutes post initiation dose.
Patients with asthma may experience reversible temporary mild bronchospasm after passing the initiation dose assessment and therefore all patients should be monitored until their FEV1 has returned to baseline levels.
Therapeutic dose regimen
The therapeutic dose regimen should not be prescribed until the initiation dose assessment has been performed. The patient must complete and pass the initiation dose assessment before starting treatment with Isotol.
A bronchodilator must be administered 5-15 minutes before each dose of Isotol.
The recommended dose of Isotol is 400 mg twice a day. This requires the inhalation of the contents of ten capsules via the inhaler device twice a day.
The doses should be taken morning and night with the evening dose taken 2-3 hours before bedtime.
For patients receiving several respiratory therapies, the recommended order is:
1. Bronchodilator
2. Isotol
3. Physiotherapy/exercise
4. Dornase alfa (if applicable)
5. Inhaled antibiotics (if applicable)
Special populations
Elderly patients (>65 years)
There are insufficient data in this population to support a recommendation for or against dose adjustment.
Renal or hepatic impairment
Isotol has not specifically been studied in patients with impaired renal and hepatic function. Available data from studies DPM-CF-301 and 302 suggest that no dose adjustments are required for these patient populations.
Paediatric population
The safety and efficacy of Isotol in children and adolescents aged 6 to 18 years has not yet been established.1 and 5.2 but no recommendation on a posology can be made.
The safety and efficacy of Isotol in children aged less than 6 years has not been established. No data are available.
Method of administration
Isotol is for inhalation use, using the inhaler provided in the pack. It must not be administered by any other route or using any other inhaler. The capsules must not be swallowed.
Each of the capsules is loaded into the device separately. The contents of the capsules are inhaled via the inhaler device with one or two breaths. After inhalation, each empty capsule is discarded before inserting the next capsule into the inhaler device with as little delay as possible between capsules.
The inhaler device is to be replaced after one week of use. If the inhaler does require cleaning, it must be ensured that the device is empty, then it should be washed in warm water and before re use, the inhaler should be allowed to thoroughly air dry.
Detailed instructions on how to use the inhaler can be found in the patient information leaflet. Patients should be advised to carefully read them.
Isotolol 10% Solution for Infusion is contra-indicated in patients presenting with:
- Pre-existing plasma hyperosmolarity.
- Severe dehydration.
- Well established anuria.
- Severe heart failure.
- Severe pulmonary congestion or pulmonary oedema.
- Active intracranial bleeding, except during craniotomy.
- Disturbance of the blood-brain barrier.
- Hypersensitivity to Isotolol.
Hypersensitivity to the active substance.
Bronchial hyperresponsiveness to inhaled mannitol.
Hypersensitivity
Anaphylactic/anaphylactoid reactions, including anaphylaxis, as well as other hypersensitivity/infusion reactions have been reported with Isotolol. Fatal outcome has been reported.
The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated.
Isotolol occurs in nature (e.g., in some fruits and vegetables) and is widely used as excipient in drugs and cosmetics. Therefore, patients may be sensitized without having received intravenous treatment with Isotolol.
CNS toxicity
CNS toxicity manifested by, e.g. confusion, lethargy, and coma has been reported in patients treated with Isotolol, in particular in the presence of impaired renal function. Fatal outcomes have been reported.
CNS toxicity may result from:
- High serum Isotolol concentrations.
- Serum hyperosmolarity resulting in intracellular dehydration within the CNS.
- Hyponatraemia or other disturbances of electrolyte and acid/base balance secondary to Isotolol administration.
At high concentrations, Isotolol may cross the blood brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis.
In patients with pre-existing compromised blood brain barrier, the risk of increasing cerebral oedema (general or focal) associated with repeated or continued use of Isotolol must be individually weighed against the expected benefits.
A rebound increase of intracranial pressure may occur several hours after the use of Isotolol. Patients with compromised blood brain barrier are at increased risk.
Risk of renal complications
Reversible, acute oligoanuric renal failure has occurred in patients with normal pre-treatment renal function, who received large intravenous doses of Isotolol.
Progressive renal damage or dysfunction, after institution of Isotolol therapy, including increasing oliguria and azotemia, has also been described.
Although the osmotic nephrosis associated with Isotolol administration is, in principle, reversible, osmotic nephrosis in general is known to potentially proceed to chronic or even end-stage renal failure.
Patients with pre-existing renal disease, or those receiving potentially nephrotoxic drugs, are at increased risk of renal failure following administration of Isotolol. Serum osmolar gap and renal function should be closely monitored and appropriate action initiated, should signs of worsening renal function appear.
Isotolol should be administered with caution to patients with severely impaired renal function. A test dose should be employed and therapy with Isotolol continued only if an adequate urine flow is achieved.
If the urine output declines during Isotolol infusion, the patient's clinical status should be closely reviewed for developing renal impairment, and the Isotolol infusion suspended, if necessary.
Risk of hypervolaemia
The cardiovascular status of the patient should be carefully evaluated before rapidly administering Isotolol 10% Solution for Infusion.
High doses and/or high rates of infusion as well as accumulation of Isotolol (due to insufficient renal excretion of Isotolol), may result in hypervolaemia, overexpansion of the extracellular fluid, which may lead to or exacerbate existing congestive heart failure.
Accumulation of Isotolol may result if urine output continues to decline during administration and this may intensify existing or latent congestive heart failure.
If the patient's cardiac or pulmonary function deteriorates, treatment should be discontinued.
Risk of water and electrolyte imbalances, hyperosmolarity
Isotolol-induced osmotic diuresis may cause or worsen dehydration/hypovolaemia and hemoconcentration. Administration of Isotolol may also cause hyperosmolarity.
In addition, depending on dosage and duration of administration, electrolyte and acid/base imbalances may result from transcellular shifts of water and electrolytes, osmotic diuresis and/or other mechanisms. Such imbalances may be severe and potentially fatal.
Imbalances that may result from Isotolol treatment include:
- Hypernatraemia, dehydration and hemoconcentration (resulting from excessive water loss).
- Hyponatraemia (Shift of sodium-free intracellular fluid into the extra cellular compartment following Isotolol infusion may lower serum sodium concentration and aggravate pre-existing hyponatraemia. Sodium may be lost in the urine).
Hyponatraemia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema, and death. Acute symptomatic hyponatraemic encephalopathy is considered a medical emergency.
The risk for developing hyponatraemia is increased, for example:
- In children.
- In elderly patients.
- In women.
- Postoperatively.
- In persons with psychogenic polydipsia.
The risk for developing encephalopathy as a complication of hyponatraemia is increased, for example:
- In paediatric patients (≤16 years of age).
- In women (in particular, premenopausal women).
- In patients with hypoxaemia.
- In patients with underlying central nervous system disease.
Hypokalaemia, hyperkalaemia, other electrolytes imbalances, metabolic acidosis and metabolic alkalosis.
Isotolol may obscure and intensify inadequate hydration and hypovolaemia.
Infusion reactions
Infusion site reactions have occurred with the use of Isotolol.
Adding other medications or using an incorrect administration technique may cause febrile reactions due to possible introduction of pyrogens.6.
Volume and electrolyte replacement before use
In patients with shock and renal dysfunction, Isotolol should not be administered until volume (fluid, blood) and electrolytes have been replaced.
Monitoring
The acid base balance, renal function and serum osmolarity must be monitored carefully when Isotolol is used.
Patients receiving Isotolol should be monitored for any deterioration in renal, cardiac or pulmonary function and treatment discontinued in the case of adverse events.
Urinary output, fluid balance, central venous pressure and electrolyte balance (in particular serum sodium and potassium levels) should be carefully monitored.
Incompatibility with blood
Isotolol should not be given concomitantly with blood because it may cause agglutination and crenation of blood cells.
Crystallization
When exposed to low temperatures, solutions of Isotolol may crystallize.
Laboratory test interferences
Isotolol can cause false low results in some tests systems for inorganic phosphorus blood concentrations.
Isotolol produces false positive results in tests for blood ethylene glycol concentrations in which Isotolol is initially oxidized to an aldehyde.
Paediatric use
Safety and effectiveness in the paediatric population have not been established in clinical studies.
Geriatric use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
Risk of air embolism
Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is completed.
Pressurizing intravenous solutions, contained in flexible plastic containers, in order to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers.
Hyperresponsiveness to mannitol
Patients must be monitored for bronchial hyperresponsiveness to inhaled mannitol during their initiation dose assessment before commencing the therapeutic dose regimen of Isotol.If the patient is unable to perform spirometry or complete the initiation dose assessment, they must not be prescribed Isotol. Hyperresponsive patients should not be prescribed the therapeutic dose regimen of Isotol.The usual precautions regarding bronchial hyperresponsiveness monitoring apply.
A patient is defined as hyperresponsive to inhaled mannitol and must not be prescribed the therapeutic dose regimen if they experience any of the following during the initiation dose assessment:
- >10% fall from baseline in SpO2 at any point of the assessment;
- FEV1 fall from baseline is >20% at 240 mg cumulative dose;
- FEV1 has fallen 20-<50% (from baseline) at the end of the assessment and does not return to <20% within 15 minutes;
- FEV1 has fallen >50% (from baseline) at the end of the assessment.
If a therapy induced hyperresponsive reaction is suspected, Isotol should be discontinued.
Bronchospasm
Bronchospasm can occur with inhalation of medicinal product and has been reported with Isotol in clinical studies, even in patients who were not hyperresponsive to the initiation dose of inhaled mannitol. Bronchospasm should be treated with a bronchodilator or as medically appropriate.
If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of Isotol outweigh the risks to the patient.
All patients should be formally reviewed after approximately six weeks of Isotol treatment to assess for signs and symptoms suggestive of active substance induced bronchospasm.
Asthma
The safety/efficacy of mannitol in patients with asthma has not been properly studied. Patients with asthma must be carefully monitored for worsening signs and symptoms of asthma after the initiation dose of Isotol.
Patients must be advised to report worsening signs and symptoms of asthma during therapeutic use to their physician. If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of Isotol outweigh the risks to the patient. Bronchospasm should be treated with a bronchodilator or as medically appropriate.
Haemoptysis
Haemoptysis has been commonly reported with Isotol in clinical studies. Isotol has not been studied in patients with a history of significant episodes of haemoptysis (>60 ml) in the previous three months. As a consequence, these patients should be carefully monitored, and Isotol should be withheld in the event of massive haemoptysis. A massive/serious haemoptysis is considered to be:
- acute bleeding >240 ml in a 24-hour period
- recurrent bleeding >100 ml/day over several days
The reinstitution or withholding of Isotol following smaller episodes of haemoptysis should be based on clinical judgement.
Cough
Cough was very commonly reported with use of Isotol in clinical studies. Patients should be trained to practice correct inhaler technique during treatment and advised to report persistent cough with the use of Isotol to their physician.
Impaired lung function
Safety and efficacy have not been demonstrated in patients with a FEV1 of less than 30% of predicted. The use of Isotol is not recommended in these patients.
Non-CF Bronchiectasis
Efficacy and safety have not been established in non-CF bronchiectasis patients. Therefore, treatment with Isotol is not recommended.
Not relevant.
Isotol has no or negligible influence on the ability to drive and use machines.
The following adverse reactions have been reported in post-marketing experience. The frequency of the adverse drug reactions listed in this section cannot be estimated from the available data.
| MedDRA System Organ Class | Adverse reaction (MedDRA Preferred Term) | Frequency |
| Immune system disorders | Allergic reaction Anaphylactic reaction including anaphylactic shock that can be manifested with skin, gastrointestinal, and severe circulatory (hypotension) and respiratory manifestations (e.g. dyspnea). Other hypersensitivity/infusion reactions, include - hypertension - pyrexia - chills - sweating - cough - musculoskeletal stiffness and myalgia - urticaria/rash - pruritus - generalized pain - discomfort - nausea - vomiting - headache | Not known |
| Metabolism and nutrition disorders | Fluid and electrolytes imbalance including - hypervolaemia - peripheral oedema - dehydration - hyponatraemia - hypernatraemia - hyperkalaemia - hypokalaemia Metabolic acidosis | Not known |
| Nervous system disorders | Headache Dizziness Rebound intracranial pressure increase CNS toxicity manifested by - Convulsions - Coma - Confusion - Lethargy | Not known |
| Eye disorders | Blurred vision | Not known |
| Cardiac disorders | Cardiac arrhythmia Congestive heart failure | Not known |
| Respiratory, thoracic and mediastinal disorders | Pulmonary oedema Rhinitis | Not known |
| Gastrointestinal disorders | Mouth dry Thirst Nausea Vomiting | Not known |
| Skin and subcutaneous tissue disorders | Skin necrosis Urticaria | Not known |
| Musculoskeletal and connective tissue disorders | Cramps | Not known |
| Renal and urinary disorders | Excessive diuresis Nephrosis osmotic Urinary retention Acute renal failure Azotemia Anuria Oliguria Polyuria | Not known |
| General disorders and administration site conditions | Chills Chest pain (angina-like chest pain) Fever Asthenia Malaise Infusion site reactions including - infusion thrombophlebitis - infusion site inflammation - infusion site pain - infusion site rash - infusion site erythema, infusion site pruritus - infusion site pruritus Compartment syndrome (associated with extravasation and swelling at the injection site) | Not known |
| Not known |
Other adverse reactions
Severe anaphylaxis with cardiac arrest, and fatal outcome.
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 the Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard
Summary of the safety profile
Initiation dose assessment
The most commonly observed adverse reaction associated with the use of Isotol during the initiation dose assessment is cough (3.6% of patients),.
The most important adverse reaction associated with the use of Isotol during the initiation dose assessment is bronchospasm.
Therapeutic dose regimen
The most commonly observed adverse reaction associated with the use of Isotol is cough. This was observed in 10.2% of patients compared to 5.0% of patients in the control arm. Cough which led to cessation of treatment was also commonly experienced and was observed in 4.7% of patients in the Isotol treatment arm.
The most important adverse reaction associated with the use of Isotol is haemoptysis. The proportion of patients who experienced haemoptysis as an adverse reaction was 7.3% and 2.9% in the Isotol arms for studies 301 and 302, respectively vs. 3.4% and 0% in the control arms. Total haemoptysis incidence including during exacerbation was 15.8% in the mannitol arm and 14.6% in the control arm.
Tabulated list of adverse reactions
Frequencies provided in Table 1 and 2 are based on the observations on the day of screening and during two pivotal comparative clinical studies investigating the effect of Isotol (safety population, 361 patients on Isotol).
Frequencies are defined as:
Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (>1/100,000 to <1/10,000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Frequency of adverse reactions with Isotol during the treatment phase and on the day of screening
| System organ class | Very common | Common | Uncommon |
| Infections and infestations | Bacterial disease carrier Oral candidiasis Staphylococcal infection | ||
| Metabolism and nutrition disorders | Decreased appetite CF related diabetes Dehydration1 | ||
| Psychiatric disorders | Initial insomnia Morbid thoughts | ||
| Nervous system disorders | Headache | Dizziness2 | |
| Ear and labyrinth disorders | Ear pain | ||
| Respiratory, thoracic and mediastinal disorders | Cough | Haemoptysis Condition aggravated2 Pharyngolaryngeal pain Cough1 Chest discomfort2 Wheezing Productive cough Throat irritation | Wheezing1 Bacteria sputum identified Asthma Rhinorrhoea Bronchospasm2 Fungus sputum test positive Dysphonia Dyspnoea Hyperventilation Obstructive airways disorder Respiratory tract congestion Sputum discoloured Bronchitis Bronchopneumonia Lung infection Pharyngitis Upper respiratory tract infection Hypoxia1 Productive cough1 Forced expiratory volume decreased1 Chest pain1 Throat irritation1 |
| Gastrointestinal disorders | Post-tussive vomiting Vomiting | Nausea2 Vomiting1 Diarrhoea1 Eructation Flatulence Gastrooesophageal reflux disease Glossodynia Retching2 Stomatitis Abdominal pain upper1 Apthous Stomatitis1 Odynophagia1 Post-tussive vomiting1 | |
| Skin and subcutaneous tissue disorders | Acne Cold sweat Pruritus Rash Rash pruritic | ||
| Musculoskeletal and connective tissue disorders | Musculoskeletal chest pain Arthralgia Back pain Joint stiffness Musculoskeletal pain | ||
| Renal and urinary disorders | Urinary incontinence | ||
| General disorders and administration site conditions | Influenza like illness Fatigue2 Hernia pain Malaise Pyrexia | ||
| Investigations | Blood alkaline phosphatase increased1 |
1Adverse reaction occurred on the day of screening
2Adverse reaction occurred both during the treatment phase and on the day of screening
Description of selected adverse reactions
Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT). In study 301, overall the most frequently reported events during the MTT were cough in 18 (4.8%) subjects, wheezing/bronchospasm in eight (2.1%) subjects and chest discomfort in six (1.6%) subjects. In study 302 the most frequent clinical sign or symptom reported during the MTT was cough (7.9%).
Paediatric population (6 to 17 years of age)
Frequency, type and severity of adverse reactions in children are similar to those observed in adults.
Initiation dose (6 to 17 years of age)
The most commonly observed adverse reaction associated with the use of Isotol during the initiation dose assessment with the paediatric population is cough (4.8% of patients).
The most important adverse reaction associated with the use of Isotol during the initiation dose assessment with the paediatric population is bronchospasm.
Therapeutic dose regimen(6 to 17 years of age)
The most commonly observed adverse reaction associated with the use of Isotol is cough. This was observed in 7.8% of patients compared to 3.8% of patients in the control arm. The most important adverse reaction associated with the use of Isotol is haemoptysis.
Table 2: Frequency of adverse reactions with Isotol during the treatment phase and on the day of screening-paediatric population (6 to 17 years of age)
| System organ class | Very common | Common | Uncommon |
| Psychiatric disorders | Initial insomnia | ||
| Nervous system disorders | Headache | Dizziness2 | |
| Ear and labyrinth disorders | Ear Pain | ||
| Respiratory, thoracic and mediastinal disorders | Cough2 Condition aggravated Haemoptysis Pharyngolaryngeal pain Bacteria sputum identified Chest discomfort Wheezing Asthma Productive cough | Bronchitis Bronchopneumonia Dysphonia Hyperventilation Sputum Discoloured Throat irritation Pharyngitis Upper respiratory tract infection Bronchospasm1 Dyspnoea Chest discomfort1 Chest pain1 | |
| Gastrointestinal disorders | Vomiting Post-tussive vomiting | Nausea2 Vomiting1 Odynophagia1 Post-tussive vomiting1 Retching1 | |
| Skin and subcutaneous tissue disorders | Pruritus Pruritic rash | ||
| Musculoskeletal and connective tissue disorders | Musculoskeletal chest pain | ||
| Renal and urinary disorders | Urinary incontinence | ||
| General disorders and administration site conditions | Pyrexia |
1Adverse reaction occurred on the day of screening
2Adverse reaction occurred both during the treatment phase and on the day of screening
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 the Yellow Card Scheme in the UK, Website: www.mhra.gov.uk/yellowcard or in Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: [email protected].
Signs and symptoms of overdose with Isotolol may include acute renal failure, electrolytes imbalance, hypervolaemia, CNS toxicity.
Prolonged administration or rapid infusion of large volumes of hyperosmotic solutions may results in circulatory overload and acidosis. Headache, nausea and shivering without temperature change may represent initial signs/symptoms. Confusion, lethargy, convulsions, stupor and coma may follow.
In case of suspected overdose, treatment with Isotolol should be stopped immediately.
Management is symptomatic and supportive, with monitoring of fluid and electrolyte balance. Isotolol is dialyzable. Haemodialysis may be helpful.
Susceptible persons may suffer bronchoconstriction in the event of an inhaled overdose. If excessive coughing and bronchoconstriction occurs, a beta2 agonist should be given, and oxygen if necessary.
Pharmacotherapeutic group: “Solutions producing osmotic diuresisâ€, ATC code: “B05BC01â€
Isotolol, a carbohydrate, is confined to the extracellular compartment. It has an osmotic effect which causes fluid to pass from the intracellular to the extracellular compartment.
Isotolol is freely filterable at the kidney glomerulus and less than 10% is reabsorbed back from the kidney tubule. Confined to the kidney tubules, Isotolol exerts an osmotic effect which prevents fluid reabsorption from the glomerular filtrate and produces diuresis. It thereby promotes urine flow in oliguria/anuria or in situations where the patient is at risk of onset of acute renal failure. Isotolol also increases electrolyte excretion, especially sodium, potassium and chloride. Excretion of renally excreted toxic substances such as aspirin and barbiturates is also increased.
Isotolol does not penetrate the blood-brain barrier under usual circumstances. Confined to the plasma, Isotolol exerts an osmotic pressure, causing fluid to leave the brain tissue, and brain volume and intracranial pressure to be reduced.
Isotolol does not penetrate the eye. Isotolol promotes excretion of aqueous humour and thereby reduces intraocular pressure.
Pharmacotherapeutic group: Cough and cold preparations, Mucolytic. ATC code: R05CB16
Mechanism of action
Isotol is an inhaled hyperosmotic medicinal product. While the exact mechanism of action is unknown, inhaled mannitol may change the viscoelastic properties of mucus, increase the hydration of the periciliary fluid layer and contribute to increased mucus clearance of the retained secretions through mucociliary activity. Productive cough can contribute to sputum clearance.
Pharmacodynamic effects
In the ITT population of an open label dose response study, DPM-CF-202, the mean (SD) percent change in FEV1 for the 400 mg dose was 8.75 (SD: 12.4) and -1.569 (SD: 9.0) for 40 mg dose (p < 0.0001).
Clinical efficacy and safety
Two Phase 3, 26-week double blind, randomised, parallel arm, controlled, intervention studies (DPM-CF-301 and DPM-CF-302) have been performed in which 324 (DPM-CF-301) and 318 (DPM-CF-302) patients aged 6 years and above were randomised in a 3:2 ratio to inhaled mannitol 400 mg twice daily or to control (inhaled mannitol 50 mg twice daily). Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT) defined as either 1) a fall in FEV1 >20% from baseline at midpoint (step 4) or 2) fall from baseline > 20 % at end of test that did not recover to < 20% within 15 minutes or 3) who had a fall in FEV1 > 50% from baseline at end of test (step 6) or 4) who had a fall in Sp02 to < 89% during the procedure. An additional 4% (n=27) of patients from the two studies had incomplete MTTs and were not randomised.
Mean (SD) baseline FEV1 percent predicted in study DPM-CF-301 (safety population, N= 295) was 62.4 (SD:16.45) and 61.4 (SD:16.13) in the mannitol and control groups, respectively. These figures for study DPM-CF-302 (N=305) are as follows: 65.24 (SD:13.90) and 64.35 (SD:15.29). In study DPM-CF-301 64.4 % of the patient population were adults while in study DPM-CF-302 this figure was 49.5%. Fifty five % of patients were receiving rhDNase in study DPM-CF-301 while in study DPM-CF-302 this number was 75%. The percentage of patients receiving inhaled antibiotics was 55% in study DPM-CF-301 and 56% in study DPM-CF-302. Concomitant administration with hypertonic saline was not permitted in these trials.
The primary pre-specified endpoint i.e. the change from baseline in FEV1 (ml) in the modified ITT (mITT) population (n=269 and 297 in studies DPM-CF-301 and DPM-CF-302, respectively) compared to control over the 26 weeks period is provided in Table 1 alongside FEV1 presented as absolute and relative change % predicted.
Table 1 - Change in FEV1 from baseline over 26 weeks in the mITT and adult populations
| Effect size estimate | ||||
| DPM-CF-301 | DPM-CF-302 | |||
| FEV1 (95% CI) | p value | FEV1 (95% CI) | p value | |
| Overall Population | ||||
| N=269 | N=297 | |||
| Absolute mL | 94.5 (46.2, 142.7) | <0.001 | 54.1 (-1.97, 110.3) | 0.059 |
| Absolute % predicted | 2.4 (0.9, 3.9) | 0.001 | 1.9 (-0.02, 3.8) | 0.052 |
| Relative % predicted | 3.5 (1.0, 6.1) | 0.007 | 3.6 (0.3, 6.9) | 0.033 |
| Adult Population | ||||
| N=171 | N=144 | |||
| Absolute mL | 108.5 (47.6, 169.4) | <0.001 | 85.9 (4.6, 167.3) | 0.038 |
| Absolute % predicted | 2.7 (0.9, 4.5) | 0.004 | 2.3 (-0.4, 5.1) | 0.095 |
| Relative % predicted | 4.3 (1.1, 7.5) | 0.008 | 5.0 (0.2, 9.8) | 0.040 |
In rhDNase users in study 301 the relative change in FEV1 % predicted from baseline across 26 weeks of treatment was 2.83 (95% CI -0.62, 6.27). For non-users the relative change was 4.30 (95% CI 0.53, 8.07). In study 302 the relative change (95% CI) for rhDNase users and non-users was 3.21 (-0.61, 7.03) and 4.73 (-1.93, 11.40), respectively.
The number of subjects with at least one protocol defined pulmonary exacerbation (PDPE, defined by the presence of at least 4 symptoms and signs plus the use of intravenous antibiotics) was 18.1% in the mannitol arm and 28% in the control arm in study 301 (ITT population). In study 302 15.2% subjects in the mannitol arm and 19% in the control had a PDPE.
The estimated effect of treatment (mean change and 95% CI from baseline over 26 weeks, mITT population) on FVC was 108.78 ml (95% CI: 49.21, 168.35) in study 301 and 71.4 ml (95% CI: 10.57, 132.13) in study 302.
Paediatric population
The safety and efficacy of Isotol in children and adolescents aged less than 18 years has not been established.
In studies DPM-CF-301 and 302 relative % predicted FEV1 compared to control in children (6-11 years) was improved by 0.44% (95% CI -5.90, 6.77, N=43) and 6.1% (95% CI -1.28, 13.54, N=59) over 26 weeks (p=0.892 and 0.104) respectively.
In adolescents (12-17 years) relative change in % predicted FEV1 compared to control improved by 3.31% (95% CI -2.29, 8.90, N=55) and 0.42% (95% CI -5.45, 6.29, N=94) over 26 weeks (p=0.245 and 0.888) respectively.
When administered intravenously, Isotolol is eliminated largely unmetabolised through the glomeruli. It is freely filtered by the glomeruli, with less than 10% tubular reabsorption and is not secreted by tubular cells. The elimination half-life in adults is approximately 2 hours, longer where renal failure is present. 80% of an intravenous dose is excreted unchanged within 3 hours.
Absorption
In a study of 18 healthy male adult volunteers, the absolute bioavailability of mannitol powder for inhalation by comparison to mannitol administered intravenously was 0.59% ± 0.15.
The rate and extent of absorption of mannitol after inhaled administration was very similar to that observed after oral administration. The Tmax after inhaled administration was 1.5 ± 0.5 hours.
In a study of 9 cystic fibrosis patients (6 adults, 3 adolescents), using 400 mg inhaled mannitol as a single dose (Day 1) then twice a day for 7 days (Days 2 - 7), pharmacokinetic parameters were similar for adults and adolescents, except for a longer average apparent terminal half life for adolescents (Day 1 = 7.29 hours, Day 7 = 6.52 hours) compared with adults (Day 1 = 6.10 hours, Day 7 = 5.42 hours). Overall, the comparison of AUCs between Day 1 and Day 7 showed a time independence of pharmacokinetics, indicating linearity at the dose level administered in this study.
Biotransformation
A small percentage of systemically absorbed mannitol undergoes hepatic metabolism to glycogen and carbon dioxide. Studies in rats, mice and humans have demonstrated that mannitol has no toxic metabolites. The metabolic pathway of inhaled mannitol was not examined in pharmacokinetic studies.
Distribution
Lung deposition studies have demonstrated a 24.7% deposition of inhaled mannitol confirming its distribution to the target organ. Nonclinical toxicology studies indicate that mannitol inhaled into the lungs is absorbed into the bloodstream, with the maximum serum concentration being achieved occurring at 1 hour. There is no evidence that mannitol is accumulated in the body, therefore distribution of inhaled mannitol was not examined in PK studies.
Elimination
The cumulative amount of mannitol filtered into the urine over the 24 hour collection period was similar for inhaled (55%) and oral (54%) mannitol. When administered intravenously, mannitol is eliminated largely unchanged by glomerular filtration and 87% of the dose is excreted in the urine within 24 hours. The mean terminal half-life in adults was approximately 4 to 5 hours from serum and approximately 3.66 hours from urine.
Paediatric population
The safety and efficacy of Isotol in children and adolescents aged 6 to 18 years has not yet been established.
The limited data available in adolescents aged 12 to 17 years indicate the pharmacokinetic parameters of inhaled mannitol are similar to the adult population.
There are no data available for children under 12 years of age.
The preclinical safety assessment of Isotolol 10% in animals is not relevant as Isotolol is a substance with well-established use in patients and is covered by appropriate pharmacopoeial references.
In male rats after 13 weeks of inhaled mannitol dosing, elevated circulating lymphocyte numbers and mandibular lymph node plasmacytosis was observed at doses greater than 9.3 fold the maximal dose. The elevated lymphocyte count was within historical control values, did not progress and was essentially resolved by the end of the in life phase of the study and following withdrawal of treatment. This effect was not noted in any other species and did not result in clinical signs.
In dogs an increased occurrence of coughing was observed both during and immediately post dose for low and high dose inhaled mannitol administration. No treatment-related adverse effect occurred greater than 13 fold the maximal therapeutic dose.
No mutagenic or genotoxic effect has been revealed when mannitol was assayed in a standard battery of genotoxicity tests.
Mannitol was shown not to be an irritant in an isolated bovine eye assay or when introduced into rabbit eyes.
No evidence of carcinogenicity was observed when dietary mannitol (≤5%) was administered to mice and rats for 2 years. Carcinogenicity studies have not been carried out with inhaled mannitol.
Reproduction and developmental toxicity studies have not been carried out with inhaled mannitol. However, studies conducted with mannitol administered via other routes indicated no effect on foetal survival in mice, rats and hamsters and on embryo and foetal development in rats and rabbits.
Animal reproduction studies have not been carried out with inhaled mannitol. However, studies conducted with orally administered mannitol indicated no teratogenic effects in mice or rats, at doses of up to 1.6 g/kg, or in hamsters at 1.2 g/kg.
Additives may be incompatible with Isotolol 10% Solution for infusion.
Incompatibility of the medicinal product to be added with the solution in the Viaflo container must be assessed before addition.
Before adding a medicinal product, verify it is soluble and stable in water at the pH of the Isotolol solution (4.5 to 7.0)
Isotolol 10% Solution for Infusion should not be administered simultaneously with, before, or after administration of blood through the same infusion equipment, due to risk of pseudoagglutination.
The Instructions for Use of the medicinal product to be added must be consulted.
As an example cefepime, imipenem, cilastin and filgrastim are incompatible with Isotolol solutions, but this list is not exhaustive. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
The addition of Potassium or Sodium Chloride to Isotolol 10% may cause precipitation of Isotolol.
Not applicable.
Use administration sets with a final in-line filter because of the potential for Isotolol crystals to form.
Additives may be introduced before infusion or during infusion through the re-sealable medication port.
Thorough and careful aseptic mixing of any additive is mandatory. Solutions containing additives should be used immediately and not stored.
Before adding a medicinal product, verify it is soluble in water at the pH of Isotolol solution.
Discard after single use.
Discard any unused portion.
Do not reconnect partially used bags.
Opening
- Remove the Viaflo container from the overpouch just before use.
- Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution, as sterility may be impaired.
- Check solution for limpidity and absence of foreign matter. If solution is not clear or contains foreign matter, discard the solution.
Preparation for administration
Use sterile material for preparation and administration.
- Suspend container from eyelet support. Remove plastic protector from outlet port at bottom of container:
| - grip the small wing on the neck of the port with one hand - grip the large wing on the cap with the other hand and twist, - the cap will pop off. |
- Use an aseptic method to set up the infusion. Attach administration set. Refer to complete directions accompanying set.
Techniques for injection of additive medicinal products
Warning: Additives may be incompatible. Check additive compatibility with both the solution and container prior to use.
To add medicinal products before administration:
- Disinfect medication site. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
Mix solution and medication thoroughly. For high-density medication such as potassium chloride, tap the ports gently while ports are upright and mix.
Caution: Do not store bags containing added medications.
To add medicinal products during administration:
1. Close clamp on the set
2. Disinfect medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from intravenous pole and/or turn to an upright position.
5. Evacuate both ports by tapping gently while the container is in an upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position, re-open the clamp and continue administration.
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
