Serious warnings and precautions: Severe, sometimes fatal, hypotension, hypoglycaemia, acute pancreatitis, renal impairment and cardiac arrhythmias have been reported. Other life threatening reactions requiring immediate corrective measures and withdrawal of treatment have included leucopenia (less than 1,000 per cubic millimetre), thrombocytopenia (less than 20,000 per cubic millimetre), acute renal failure, hypocalcaemia, and ventricular tachycardia. A possible case of Stevens-Johnson syndrome has been reported.
Fatalities have been documented following pentamidine administration. The ratio of therapeutic to toxic dose of pentamidine is very low and adverse effects, some of which may be life threatening, occur frequently during its use. Pentamidine Isethionate for Injection should be used only in a hospital setting with facilities to monitor blood glucose, blood count, renal function and hepatic function. Electrocardiograms should be carried out at regular intervals (see Monitoring and Laboratory Tests as follows).
Extravasation reactions may result in ulceration, tissue necrosis and long-term sequelae (see Adverse Reactions).
DBL Pentamidine is not approved for inhaled use. Bronchospasm has been reported to occur following the use of inhaled product (see Adverse Reactions). This has been particularly noted in patients who have a history of smoking or asthma. This can be controlled by prior use of bronchodilators.
Pentamidine isethionate should be used with caution in patients with the following: Malnutrition; Hyperglycaemia or hypoglycaemia; Hepatic dysfunction; Renal dysfunction; Hypertension or hypotension; Anaemia, leucopenia or thrombocytopenia.
General: Pentamidine Isethionate for Injection should only be administered under close medical supervision, and the patient should be very carefully monitored for the development of serious adverse reactions (see Adverse Reactions).
The administration of Pentamidine Isethionate for Injection should be limited to patients in whom Pneumocystis jirovecii infection has been confirmed.
Some patients may become nauseated or develop fever after taking each dose of Pentamidine Isethionate for Injection. In such cases, the prophylactic use of an antiemetic and/or paracetamol may be considered.
Cardiovascular: Patients may develop sudden, severe hypotension after receiving a single intramuscular or intravenous dose of pentamidine isethionate. Therefore, patients receiving Pentamidine Isethionate for Injection should be in a supine position and the blood pressure monitored closely during administration of the drug and several times thereafter until the blood pressure is stable. Equipment for emergency resuscitation should be readily available. Pentamidine isethionate for Injection should be infused over a period of at least 60 minutes to minimise the risk of hypotension.
Severe hypotension with accompanying bradycardia has been observed in a patient after the sixth dose of pentamidine isethionate. This hypotension did not respond to intravenous colloids, graded compression stockings or corticosteroids but resolved within four days of stopping treatment.
Ventricular tachycardia and ECG abnormalities including QT interval prolongation and torsade de pointes may develop in patients receiving pentamidine isethionate. ECG's may be required at regular intervals if signs of cardiotoxicity develop.
Endocrine and Metabolism: Pentamidine isethionate can produce hypoglycaemia, which may be severe, life-threatening and/or prolonged. It generally occurs after 5 to 7 days of therapy but can even occur up to several days after the drug is discontinued. The duration appears quite variable, persisting for one day to several weeks. Pentamidine isethionate-induced hypoglycemia has been associated with pancreatic islet cell necrosis and inappropriately high plasma insulin concentrations. Hyperglycemia and diabetes mellitus, with or without preceding hypoglycemia, have also occurred, sometimes several months after termination of therapy with pentamidine isethionate.
Hypoglycaemia induced by pentamidine isethionate may be controlled by intravenous administration of dextrose or (oral) diazoxide, but it is not known if such therapy can prevent the subsequent development of diabetes mellitus.
Gastrointestinal: Cases of nausea and vomiting have been observed with pentamidine isethionate treatment.
Haematologic: Leucopenia and thrombocytopenia, which can be severe (e.g. leucocyte count less than 1,000 per cubic millimetre, platelet count less than 20,000 per cubic millimetre), occur occasionally in patients receiving pentamidine isethionate. Cases of anaemia have been observed. In a few cases, pentamidine isethionate therapy has been associated with neutropenia.
Hepatic/Biliary/Pancreatic: Abnormal liver function tests may occur. Liver function should be routinely monitored in patients receiving Pentamidine Isethionate for Injection (see Monitoring and laboratory tests as follows). Cases of acute pancreatitis have been observed with pentamidine isethionate treatment.
Immune: Hypersensitivity reactions at the injection site, such as skin rash and erythema, may occur (see Skin as follows and Adverse Reactions).
Skin: Intramuscular injections are often associated with pain, tenderness, erythema, and induration at the site of injection. Sterile abscesses have been observed. Therefore, intramuscular administration should be reserved for patients with adequate muscle mass and limited to rare situations where intravenous infusion is not feasible.
Vascular: Phlebitis can occur after intravenous injection.
Monitoring and Laboratory Tests: In order to monitor for possible toxicity, the following tests should be performed before, during and after treatment.
1. Blood urea nitrogen and serum creatinine daily during therapy.
2. Complete blood and platelet counts daily during therapy.
3. Fasting blood glucose measurements should be taken before, daily during therapy, and at regular intervals after completion of therapy. Hyperglycaemia and diabetes mellitus, with or without preceding hypoglycaemia, have occurred up to several months after cessation of therapy.
4. Liver function tests (LFTs) including serum bilirubin, alkaline phosphatase, aspartate aminotransferase (AST/SGOT), and alanine aminotransferase (ALT/SGPT). If baseline measurements are normal and remain so during therapy, test weekly thereafter. When there is baseline elevation in LFTs or LFTs increase during therapy, continue monitoring weekly unless the patient is on other hepatotoxic agents, when monitoring every 3 to 5 days is appropriate.
5. Serum calcium, test weekly.
6. Urine analysis and serum electrolytes daily during therapy.
7. Electrocardiograms at regular intervals.
Effects on laboratory tests: No data available.
Effects on ability to drive and use machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in renal impairment: Severe renal impairment resulting in death may also occur in the presence of various clinical complications (e.g. bacterial sepsis), concurrent administration of other nephrotoxic antibiotic agents or previous evidence of renal disease.
Use in Children: The safety and efficacy of Pentamidine Isethionate for Injection has not been established in the paediatric population, and pharmacokinetic data are extremely limited.
Use in the Elderly: There is no information on the safe use of pentamidine in the elderly.