Mannitol

The safety/efficacy of mannitol in patients with asthma has not been formally studied. Patients with asthma must be carefully monitored for worsening signs and symptoms of asthma after the initiation dose of mannitol.

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 mannitol outweigh the risks to the patient. Bronchospasm should be treated with a bronchodilator or as medically appropriate.

Anaphylactic/anaphylactoid reactions, including anaphylaxis, as well as other hypersensitivity/infusion reactions have been reported with mannitol. Fatal outcome has been reported.

The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develops. Appropriate therapeutic countermeasures must be instituted as clinically indicated.

Mannitol occurs in nature (e.g., in some fruits and vegetables) and is widely used as an excipient in drugs and cosmetics. Therefore, patients may be sensitized without having received intravenous treatment with mannitol.

CNS toxicity manifested by, e.g. confusion, lethargy, coma has been reported in patients treated with mannitol, in particular in the presence of impaired renal function. Fatal outcomes have been reported.

CNS toxicity may result from:

• High serum mannitol concentrations
• Serum hyperosmolarity resulting in intracellular dehydration within the CNS
• Hyponatraemia or other disturbances of electrolyte and acid/base balance secondary to mannitol administration.

At high concentrations, mannitol 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 preexisting compromised blood brain barrier, the risk of increasing cerebral oedema (general or focal) associated with repeated or continued use of mannitol must be individually weighed against the expected benefits.

A rebound increase of intracranial pressure may occur several hours after the use of mannitol. Patients with compromised blood brain barrier are at increased risk.

Cough was commonly reported with use of mannitol in clinical studies. Patients should be trained to practice correct inhaler technique during treatment and advised to report persistent cough with the use of mannitol to their physician.

Haemoptysis has been commonly reported with mannitol in clinical studies. Mannitol 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 mannitol 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 mannitol following smaller episodes of haemoptysis should be based on clinical judgement.

Bronchospasm can occur with inhalation of medicinal product and has been reported with mannitol 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 mannitol outweigh the risks to the patient.

All patients should be formally reviewed after approximately six weeks of mannitol treatment to assess for signs and symptoms suggestive of active substance induced bronchospasm.

There are limited data from the use of mannitol in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As the effects of a possible hyperresponsive reaction on the mother and/or foetus are unknown, caution should be exercised when prescribing mannitol to pregnant women. As a precautionary measure, it is preferable to avoid the use of mannitol during pregnancy.

It is unknown whether mannitol is excreted in human milk. The excretion of mannitol in milk has not been studied in animals. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast feeding or to discontinue mannitol therapy taking into account the benefit of breast feeding for the child and the benefit of mannitol therapy for the woman.

Fertility

For mannitol no clinical data on fertility is available. Animal reproduction studies have not been carried out with inhaled mannitol. However, studies with orally administered mannitol indicate no fertility effects.

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