Pentamidine (injection)

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# Overview
Pentamidine (injection) is an anti-protozoal agent that is FDA approved for the treatment of pneumonia due to Pneumocystis carinii.   Common adverse reactions include rash, loss of appetite, nausea, increased liver function test, and nephrotoxicity.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

## Indications
Pentam 300 (pentamidine isethionate for injection) is indicated for the treatment of pneumonia due to Pneumocystis carinii.

## Dosage
Pentamidine isethionate should be administered IM or IV only.  The recommended regimen for adults and pediatric patients beyond 4 months of age is 4 mg/kg once a day for 14 to 21 days.  Therapy for longer than 21 days with pentamidine isethionate has also been used but may be associated with increased toxicity.

### Intramuscular Injection
The contents of one vial (300 mg) should be dissolved in 3 mL of Sterile Water for Injection, USP at 22 - 30C (72 - 86F).  The calculated daily dose should then be withdrawn and administered by deep IM injection.

### Intravenous Injection
The contents of one vial (300 mg) should first be dissolved in 3 to 5 mL of Sterile Water for Injection, USP, or 5% Dextrose Injection, USP at 22- 30C (72 - 86F).  The calculated dose of pentamidine isethionate should then be withdrawn and diluted further in 50 to 250 mL of 5% Dextrose Injection, USP.
The diluted IV solutions containing pentamidine isethionate should be infused over a period of 60 to 120 minutes.
Aseptic technique should be employed in preparation of all solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

### Stability
After reconstitution with sterile water, the Pentam solution is stable for 48 hours in the original vial at room temperature if protected from light.  To avoid crystallization,store at 22 - 30C (72 - 86F).  Intravenous infusion solutions of pentamidine isethionate at 1 mg/mL and 2.5 mg/mL prepared in 5% Dextrose Injection, USP are stable at room temperature for up to 24 hours.
Intravenous (IV) solutions of pentamidine isethionate have been shown to be incompatible with fluconazole and foscarnet sodium.  IV solutions of pentamidine isethionate have been shown to be compatible with IV solutions of zidovudine (AZT) and diltiazem hydrochloride.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Treatment of Pneumocystis pneumonia in HIV-infected hosts
- Intravenous pentamidine 3 milligrams/kilogram

### NonGuideline-Supported Use
- Prophylaxis of Pneumocystis pneumonia in HIV-infected hosts
- Intramuscular 300 milligrams given monthly
- Cutaneous leishmaniasis
- Intramuscular pentamidine, 4 milligrams/kilogram (mg/kg) on days 1, 3, and 5
- Intramuscular pentamidine 450 mg  on days 1 and 3
- Trypanosomiasis
- Pentamidine 4 milligrams/kilogram every other day deep intramuscular injection for a total of 10 injections per patient
- Visceral leishmaniasis
- Intramuscular pentamidine, 4 milligrams/kilogram (mg/kg) on days 1, 3, and 5
- Intramuscular pentamidine 450 mg  on days 1 and 3

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
The recommended regimen for adults and pediatric patients beyond 4 months of age is 4 mg/kg once a day for 14 to 21 days.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentamidine (injection) in pediatric patients.

### NonGuideline-Supported Use
- Prophylaxis of Pneumocystis pneumonia in HIV-infected hosts
- Cutaneous leishmaniasis
- Trypanosomiasis
- Visceral leishmaniasis

# Contraindications
Contraindicated in patients with a history of hypersensitivity to pentamidine isethionate.

# Warnings
Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate, both by the IM and IV routes.  Severe hypotension may result after a single IM or IV dose and is more likely with rapid IV administration. The administration of the drug should, therefore, be limited to the patients in whom Pneumocystis carinii has been demonstrated.  Patients should be closely monitored for the development of serious adverse reactions.
Extravasations have been reported which, in some instances, proceeded to ulceration, tissue necrosis and/or sloughing at the injection site.  While not common, surgical debridement and skin grafting has been necessary in some of these cases; long-term sequelae have been reported.  Prevention is the most effective means of limiting the severity of extravasation.  The intravenous needle or catheter must be properly positioned and closely observed throughout the period of pentamidine isethionate administration.  If extravasation occurs, the injection should be discontinued immediately and restarted in another vein.  Because there are no known local treatment measures which have proven to be useful, management of the extravasation should be symptomatic.

# Adverse Reactions

## Clinical Trials Experience
Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate, both by the IM and IV routes.  Nephrotoxic events (increased creatinine, impaired renal function, azotemia, and renal failure) are common with the parenteral administration of pentamidine isethionate.  The administration of the drug should, therefore, be limited to the patients in whom Pneumocystis carinii has been demonstrated.
The most frequently reported spontaneous adverse events (1 to 30%) reported in clinical trials, regardless of their relation to pentamidine isethionate therapy were as follows (n=424):
Adverse events with a frequency of less than 1% incidence were as follows (No causal relationship to treatment has been established for these adverse events):

## Postmarketing Experience
From post-marketing clinical experience with pentamidine isethionate, the following adverse events have been reported: cough, diabetes mellitus/ketoacidosis, dyspnea, infiltration, and torsades de pointes.

# Drug Interactions
No drug interaction studies with Pentam 300 have been conducted.
Because the nephrotoxic effects may be additive, the concomitant or sequential use of pentamidine isethionate and other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, foscarnet, or vancomycin should be closely monitored and avoided, if possible.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with pentamidine isethionate.  It is also not known whether pentamidine isethionate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  Pentamidine isethionate should not be given to a pregnant woman unless the potential benefits are judged to outweigh the unknown risks.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentamidine (injection) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Pentamidine (injection) during labor and delivery.

### Nursing Mothers
It is not known whether pentamidine isethionate is excreted in human milk.  Because of the potential for serious adverse reactions in nursing infants from pentamidine isethionate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.  Because many drugs are excreted in human milk, pentamidine isethionate should not be given to a nursing mother unless the potential benefits are judged to outweigh the unknown risks.

### Pediatric Use
Intravenous and intramuscular pentamidine has been described as an effective treatment for Pneumocystis carinii pneumonia (PCP) in immunocompromised pediatric patients beyond 4 months of age.  The efficacy and safety profiles in these pediatric patients were similar to those observed in adult patients.

### Geriatic Use
There is no FDA guidance on the use of Pentamidine (injection) in geriatric settings.

### Gender
There is no FDA guidance on the use of Pentamidine (injection) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Pentamidine (injection) with respect to specific racial populations.

### Renal Impairment
The efficacy or safety of alternative Pentam 300 dosing protocols have not been established for patients with impaired renal or hepatic function.

### Hepatic Impairment
There is no FDA guidance on the use of Pentamidine (injection) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pentamidine (injection) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Pentamidine (injection) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intramuscular
- Intravenous

### Monitoring
- Symptomatic improvement
- CBC, platelet counts, serum calcium concentrations, hepatic function, and ECG; before, during and after therapy
- Daily BUN, serum creatinine, and blood glucose levels; before, during and after therapy

# IV Compatibility
There is limited information regarding the compatibility of Pentamidine (injection) and IV administrations.

# Overdosage
A 17 month old infant inadvertently received 1600 mg of intravenous pentamidine isethionate which was followed by renal and hepatic function impairment, hypotension and cardiopulmonary arrest.  Treatment included cardiopulmonary resuscitation, epinephrine, atropine and intubation.  In addition, a four hour course of charcoal hemoperfusion was accompanied by reduction of pentamidine serum concentration and stabilization of the patients condition.  The patient recovered from these adverse events, but later died due to an unknown cause.

# Pharmacology

## Mechanism of Action
Pentamidine isethionate, an aromatic diamidine, is known to have activity against Pneumocystis carinii.  The mode of action of pentamidine is not fully understood.  In vitro studies indicate that the drug interferes with protozoal nuclear metabolism by inhibition of DNA, RNA, phospholipid and protein synthesis.

## Structure
Pentam 300 (pentamidine isethionate for injection), an anti-protozoal agent, is a sterile, nonpyrogenic, lyophilized product.  After reconstitution, it should be administered by intramuscular (IM) or intravenous (IV) routes (see DOSAGE AND ADMINISTRATION).  Pentamidine isethionate is a white crystalline powder soluble in water and glycerin, slightly soluble in alcohol and insoluble in ether, acetone, and chloroform.  It is chemically designated as 4,4-bis-benzenecarboximidamid with the following structural formula:
Each vial contains: 
Pentamidine isethionate . . . . . . . . . . . . . 300 mg

## Pharmacodynamics
There is limited information regarding Pentamidine (injection) Pharmacodynamics in the drug label.

## Pharmacokinetics
Pharmacokinetic parameters following the administration of 4 mg/kg pentamidine isethionate as a single two-hour intravenous infusion or after a single intramuscular injection to 12 patients with AIDS are presented in the following table:
In seven patients treated with daily IM doses of pentamidine at 4 mg/kg for 10 to 12 days, plasma concentrations were between 300 to 500 ng/mL.  The concentrations did not appreciably change with time after injection or from day to day.  Higher plasma concentrations were encountered in patients with an elevated blood urea nitrogen.  The patients continued to excrete decreasing amounts of pentamidine in urine up to 6 to 8 weeks after cessation of the treatment.
Following multiple intravenous administration of pentamidine isethionate (3.7 to 4 mg/kg/day infused over 4 hours) to 6 patients with AIDS being treated for PCP, the pharmacokinetic parameters obtained on Days 1,4 and 7 are summarized in the following table:
- derived from Lidman
Compared to the mean AUC on Day 1, AUC on Day 4 and Day 7 were about 2 and 3 fold higher, respectively, suggesting that steady state was not achieved by Day 7 of dosing.
In other published reports of pharmacokinetics of pentamidine following daily intravenous doses of 2 to 4 mg/kg/day, clearance ranged from 30 to 40 mL/min/kg and Vdss ranged from 200 to 400 L/kg.  Reported values for terminal half-lives of 2.8 to 12 days is suggestive of a deep peripheral compartment.  In the urine, up to 12% of the administered dose has been recovered during a dosing interval as unchanged pentamidine.
Tissue distribution was studied in mice given a single intraperitoneal injection of pentamidine at 10 mg/kg.  The concentration was highest in the kidneys followed by the liver.  In mice, pentamidine was excreted unchanged, primarily via the kidneys with some elimination in the feces.  The ratio of amounts excreted in the urine and feces (4:1) was constant over the period of study.
Tissue distribution has also been studied in normal and in renally impaired dogs (N = 3 each) given 13 mg/kg of pentamidine IV, in 2 doses separated by five weeks.  The concentration of pentamidine was highest in the liver followed by kidneys and lungs.  Pentamidine was concentrated in these organs approximately 70 to 1000 times that of the peak serum concentration.  Similar findings were reported in normal and in renally impaired dogs (N = 2 each) given 97.5 mg/kg of pentamidine IV, in 15 daily doses.  After repeated doses, the organs showed a further 3 to 7 fold accumulation while serum concentrations remained unchanged.

## Nonclinical Toxicology
There is limited information regarding Pentamidine (injection) Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Pentamidine (injection) Clinical Studies in the drug label.

# How Supplied

## Storage
Store dry product at 20 to 25C (68 to 77F) . Protect from light.
Preservative Free.  Discard unused portion.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pentamidine (injection) in the drug label.

# Precautions with Alcohol
Alcohol-Pentamidine (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- PENTAM 300 

# Look-Alike Drug Names
There is limited information regarding Pentamidine (injection) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price