Pentacarinat (Pentamidine Isethionate)

PENTACARINAT®

Rhône-Poulenc Rorer

Pentamidine Isethionate

Antiparasitic Agent

Action And Clinical Pharmacology: Pentamidine isethionate is a member of a class of compounds known as an aromatic diamidines. The precise mechanism of antiprotozoal action of pentamidine isethionate has not been fully elucidated. Several mechanisms of action have been suggested including inhibition of DNA, RNA, phospholipid and protein synthesis, but the relative role of each mechanism to the overall antiprotozoal activity may vary for different types of protozoa. In vitro, pentamidine appears to have a direct cidal effect on P. carinii although the drug only moderately inhibits glucose metabolism, protein synthesis, RNA synthesis and intracellular amino acid transport.

Following administration of a single 4 mg/kg i.m. or i.v. dose of pentamidine isethionate in humans, peak plasma concentrations averaged 209 ng/mL approximately 40 minutes after the i.m. dose and 612 ng/mL after completion of a 2-hour infusion. Following daily i.m. or i.v. doses of 4 mg/kg, there appeared to be little variation in plasma concentrations from day to day and little increase with successive doses, although one study found increased trough concentrations and drug accumulation with multiple dosing.

Following oral inhalation of pentamidine isethionate via nebulization, broncho-alveolar concentrations of the drug were substantially higher than those attained following a comparable i.v. dose, while plasma concentrations were substantially lower; pentamidine appears to undergo limited absorption from the respiratory tract into the systemic circulation. Pentamidine appears to be extensively distributed and/or bound to body tissues. Following i.m. and i.v. administration of a single 4 mg/kg dose in patients with a normal kidney function, plasma concentrations declined in a biphasic manner with terminal elimination half-lives of 9.4 and 6.4 hours, respectively.

After repeated i.m. administration for 10 to 12 days, approximately 15% to 20% of the daily dose was recovered in the urine, apparently as unchanged drug. Pentamidine appears to be eliminated very slowly from tissues in which it accumulates (i.e. liver, lungs) and decreasing amounts of the drug could be detected in the urine for 6 to 8 weeks after cessation of therapy.

The extent of pentamidine distribution and accumulation following chronic inhalation therapy is not known.

In a series of patients treated for P. carinii pneumonia, the highest plasma pentamidine concentrations were found in those with elevated BUN levels. Since the major route of elimination is renal, the activity of pentamidine should be anticipated to be prolonged in the presence of severe renal function impairment. No pharmacokinetic data are available following oral inhalation of pentamidine in patients with impaired hepatic or renal function.

Indications And Clinical Uses: The therapeutic role of pentamidine and its prophylactic efficacy and long-term safety, relative to alternative therapies, in the treatment and prevention of pneumonia due to P. carinii has not been established. Comparative data are required.

Inhalation: For the prevention of P. carinii pneumonia (PCP) in high-risk, HIV-infected patients defined by one or both of the following criteria: i) a history of one or more episodes of PCP; ii) a peripheral CD4+ (T4 helper/inducer) lymphocyte count less than or equal to 200/mmor CD4 less than 20% of lymphocyte count.

These indications are based on the results of an 18-month randomized, dose-response trial in high-risk HIV-infected patients and on existing epidemiological data from natural history studies.

Injection: For the treatment of pneumonia due to P. carinii (PCP).

Contra-Indications: Patients with a history of hypersensitivity to the drug or to any of its salts.

Manufacturers’ Warnings In Clinical States: Inhalation: Cases of acute pancreatitis have been reported in patients receiving aerosolized pentamidine. Pentamidine isethionate for inhalation should be discontinued if signs or symptoms of acute pancreatitis develop.

Rare cases of renal insufficiency and acute renal failure have also been reported in association with aerosolized pentamidine.

Injection: Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine by both the i.m. and i.v. routes. Profound severe hypotension may result after a single dose (see Precautions). Severe life-threatening hypoglycemia can occur even after completion of therapy with pentamidine. 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. The parenteral administration of pentamidine, therefore, should be limited to patients in whom a diagnosis of P. carinii pneumonia has been made.

Pentamidine injection should be used only in a hospital setting with facilities to monitor blood glucose, blood count and renal and hepatic functions (see Precautions).

Pentamidine should only be administered by injection under close supervision and the patient should be very carefully monitored for the development of serious adverse reactions (see Precautions and Adverse Effects). Precautions

Precautions: Pregnancy: Pentamidine should be used during pregnancy only if clearly indicated. It is not known whether pentamidine can cause fetal harm when administered to pregnant women; however, in a teratogenicity study in rabbits, the drug was embryotoxic as evidenced by the number of post-implantation losses and by delayed ossification.

Lactation: It is not known whether pentamidine is excreted in breast milk. Because many drugs are excreted in human milk, the drug should be used with caution in nursing mothers and cessation of nursing should be considered.

Children: Efficacy and safety of aerosolized pentamidine in children have not been clearly established.

Inhalation: Prior to initiating pentamidine prophylaxis, symptomatic patients should be investigated to exclude the presence of PCP. The recommended prophylactic dosage of pentamidine is insufficient to treat acute PCP.

The potential for development of acute PCP still exists in patients receiving aerosolized pentamidine prophylactically. Therefore, any patient with symptoms suggestive of PCP, including but not limited to dyspnea, fever or cough, should be evaluated for possible acute infection and treated appropriately. The use of aerosolized pentamidine may alter the clinical and radiographic features of PCP and could result in an atypical presentation, including but not limited to mild disease or focal infection.

Prophylactic therapy with aerosolized pentamidine does not prevent dissemination of P. carinii to extrapulmonary sites. Physicians should be aware of the possibility of such dissemination. Patients with signs of disseminated disease should be investigated aggressively even if they have no signs of lung infection.

Pulmonary: Inhalation of pentamidine may induce bronchospasm or cough. This has been noted particularly in some patients who have a history of smoking or asthma. In clinical trials, cough and bronchospasm were the most frequently reported adverse experiences associated with pentamidine aerosol administration (38% and 15%, respectively, of patients receiving the 300 mg dose); however less than 1% of the doses were interrupted or terminated due to these effects. For the majority of patients, cough and bronchospasm were controlled by administration of an aerosolized bronchodilator. In patients who experience bronchospasm or cough, administration of an inhaled bronchodilator prior to giving each pentamidine dose may minimize recurrence of the symptoms.

During treatment some patients experience a burning sensation in the back of their throat. This can usually be alleviated if the patient interrupts treatment to drink some liquid.

General: Although the administration of pentamidine is reported to result in minimal systemic absorption, the extent and consequence of pentamidine accumulation following chronic inhalation therapy are not known. As a result, patients receiving pentamidine should be closely monitored for the development of serious adverse reactions that have occurred in patients receiving parenteral pentamidine, including hypotension, hypoglycemia, pancreatitis, hyperglycemia, hypocalcemia, anemia, thrombocytopenia, leukopenia, hepatic or renal dysfunction, ventricular tachycardia and Stevens-Johnson’s syndrome.

Drug Interactions: While specific studies of drug interactions with pentamidine have not been conducted, the majority of patients in clinical trials received concomitant medications, including zidovudine, with no reported interactions.

Environmental and occupational exposure: The administration of aerosolized pentamidine has raised questions regarding the safety of health care providers. These questions have addressed two basic concerns. 1) Direct toxicity: There have been reports of mucous membrane irritation (including chemical conjunctivitis) in care givers with close aerosol exposure and one case report noting a transient decrease in diffusing capacity in a therapist administering aerosolized pentamidine. Studies of ambient pentamidine concentrations when using a closed nebulizer system such as Respirgard II have reported very low levels in treatment areas, especially when nebulizer exhalation filters are used and attention is paid to turning off nebulizers when not in use. 2) Infectious exposure: Aerosolized pentamidine can be irritating to the tracheo-bronchial tree and, thereby, induces coughing in patients. Since HIV-infected patients can have potentially communicable respiratory infections (notably tuberculosis) concurrently, there exists the possibility that care givers may become exposed to potential respiratory infectious agents during the prophylactic administration of inhaled pentamidine. Consequently, careful screening of patients for infectious diseases (especially tuberculosis) and the use of expiratory filters in well-ventilated rooms are recommended. To reduce the risk of exposing health care providers to aerosolized pentamidine or potential respiratory infectious pathogens, the guidelines for administration of aerosolized pentamidine must be adhered to closely (see Dosage).

Injection: General: Pentamidine should be used with caution in patients with hypertension, hypotension, hypoglycemia, hyperglycemia, hypocalcemia, leukopenia, thrombocytopenia, anemia, and hepatic or renal dysfunction.

Patients may develop sudden, severe hypotension after receiving a single dose of pentamidine injection. Therefore, patients receiving the drug 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 should be infused over a period of at least 60 minutes and preferably over 2 to 3 hours to minimize 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 i.v. colloids, graded compression stockings or corticosteroids but resolved within 4 days of stopping treatment.

Ventricular tachycardia and ECG abnormalities have also been reported in patients receiving pentamidine. ECGs may be required at regular intervals if signs of cardiotoxicity develop.

Pentamidine can produce hypoglycemia which may be severe 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 1 day up to several weeks. Pentamidine-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. Hypoglycemia induced by pentamidine isethionate may be controlled by administration of i.v. dextrose or (oral) diazoxide but it is not known if such therapy can prevent the subsequent development of diabetes mellitus.

Leukopenia and thrombocytopenia, which can be severe (e.g. leukocyte count less than 1 000/mm platelet count less than 20 000/mm, occur occasionally in patients receiving pentamidine. Anemia occurs rarely. In a few cases, pentamidine therapy has been associated with neutropenia.

Some patients may become nauseated or febrile after each injection of pentamidine. In such cases, the prophylactic use of an antiemetic and/or antipyretic (e.g. acetaminophen) may be considered.

Phlebitis can occur after i.v. injection.

Patient Monitoring: In order to monitor for possible toxicity, the following tests should be carried out before, during and after therapy: routine determinations of blood urea nitrogen (BUN), serum creatinine and serum electrolytes; daily blood glucose determinations during therapy and continuing several times after completion of therapy as required by clinical condition; twice weekly complete blood count and platelet count; liver function tests including bilirubin, alkaline phosphatase, ALT and AST, weekly or more frequently if indicated; weekly serum calcium determinations; ECGs as indicated.

Drug Interactions: There are no documented interactions of pentamidine with other medications. However, since nephrotoxic effects may be additive, the concurrent or sequential use of pentamidine with drugs having a nephrotoxic potential (e.g. aminoglycosides, amphotericin B, cisplatin or vancomycin) should be undertaken with caution. Pentamidine should be administered with caution to patients who are receiving drugs with hepatotoxic potential, drugs with potential pancreatic toxicity (e.g. 2′, 3-dideoxyinosine [DDI]) or medication that can impair the hematopoietic system.

I.M. Administration: I.M. injections are often associated with pain, tenderness, erythema, and induration at the site of injection. Sterile abscesses have been noted. Therefore, i.m. administration should be reserved for patients with adequate muscle mass and limited to the rare situations where i.v. infusion is not feasible.

Adverse Reactions: Inhalation: The most frequent adverse effects attibutable to the inhalation of pentamidine are cough and bronchospasm (reported by 38% and 15%, respectively, of patients receiving 300 mg every 4 weeks.

The most frequently reported adverse experiences in controlled clinical trials using the Respirgard II nebulizer were as follows: 53 to 72%: fatigue, bad (metallic) taste, shortness of breath and decreased appetite; 31 to 47%: dizziness and rash; 10 to 23%: nausea, pharyngitis, chest pain or congestion, night sweats, chills and vomiting.

In nearly all cases, no conclusions were drawn as to the relationship of adverse experiences (or their severity) to treatment or underlying disease.

Other less frequently occurring adverse experiences (reported by greater than 1% and up to 5% of patients in 2 clinical trials) were pneumothorax, diarrhea, headache, anemia (generally associated with the use of zidovudine), myalgia, abdominal pain and edema.

From a total experience with 1 130 patients, adverse events reported with a frequency of 1% or less were as follows. No causal relationship to treatment was established.

General: allergic reactions and extrapulmonary pneumocystosis.

Cardiovascular: tachycardia, hypotension, hypertension, palpitations, syncope, cerebrovascular accident, vasodilation and vasculitis.

Metabolic: hypoglycemia, hyperglycemia and hypocalcemia.

Gastrointestinal: gingivitis, dyspepsia, oral ulcer/abscess, gastritis, gastric ulcer, hypersalivation, dry mouth, splenomegaly, melena, hematochezia, esophagitis, colitis and acute pancreatitis.

Hematological: pancytopenia, neutropenia, eosinophilia, and thrombocytopenia.

Hepatorenal: hepatitis, hepatomegaly, hepatic dysfunction, renal failure, flank pain and nephritis.

Musculoskeletal: arthralgia.

Neurological: tremors, confusion, anxiety, memory loss, seizure, neuropathy, paresthesia, hypesthesia, drowsiness, emotional lability, vertigo, paranoia, neuralgia, hallucination, depression and unsteady gait.

Respiratory: rhinitis, laryngitis, laryngospasm, hyperventilation, hemoptysis, gagging, eosinophilic or interstitial pneumonitis, pleuritis, cyanosis, tachypnea and rales.

Skin: pruritus, erythema, dry skin, desquamation and urticaria.

Special senses: eye discomfort, conjunctivitis, blurred vision, blepharitis and loss of taste and smell.

Urogenital: incontinence.

Reproductive: miscarriage.

Injection: Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate injection. The parenteral administration of pentamidine should therefore, be limited to patients in whom the presence of P. carinii has been demonstrated by laboratory means or by clinical diagnosis where the patient cannot tolerate an invasive procedure.

The most commonly reported and often the most serious adverse reaction is nephrotoxicity. It usually occurs as mild azotemia and/or increased serum creatinine level, reversible upon discontinuation of the drug; however, acute renal failure or severe renal insufficiency has only been occasionally observed.

Other severe and potentially lethal reactions include: hypotension, hypoglycemia and cardiac arrhythmias (see Warnings).

The following list of adverse effects is based on the largest series reported in the medical literature and on the review of the medical records of 341 patients who received pentamidine in Canada for P. carinii pneumonia, mainly by the i.v. route.

The number of patients with adverse reactions in the literature was 46.8% and in Canada was 58.1%. Adverse reactions requiring discontinuation of therapy: not available in the literature; 5.9% in the Canadian Series.

In the following information, a ( ) will be used to denote the incidence of adverse reactions in the literature and a (( )) will be used to denote the incidence of adverse reactions in the Canadian series (Data on file Rhône-Poulenc Rorer Canada Inc.).

Renal: azotemia, elevated creatinine level, renal insufficiency (23% of treated patients) ((21.7% of treated patients)).

Hepatic: increased AST, ALT, alkaline phosphatase or bilirubin (9.6%) ((10.6%)).

Hypoglycemia or diabetogenic effect (6.2%), ((7.6%)).

Cardiovascular: hypotension or syncope, ventricular tachycardia, ECG abnormalities (9.6%) ((8.8%)).

Hematologic: leukopenia, neutropenia, thrombocytopenia, rarely anemia (4.2%) ((21.4%)).

Allergic: drug fever, erythematous rash, maculopapular rash, unspecified rash, urticaria (1.5%) ((3.8%)).

Local Reactions: pain, erythema, rash, induration at i.m. injection site, sterile abscess, myonecrosis or phlebitis after i.v. injection (18%) ((2.3%)).

CNS: dizziness, headache, altered mental state, loss of consciousness, spasticity of lower extremities, convulsions, paresthesia (N/A) ((2.3%)).

Special Senses: buzzing in ears, metallic taste (N/A) ((less than 1%)).

Gastrointestinal: nausea, vomiting, anorexia, diarrhea ((8.2%)).

Increased amylase level ((less than 1%)), hyponatremia ((less than 1%)), hypocalcemia (1.2%) ((less than 1%)), bleeding ((less than 1%)), other not specified (11.1%).

Note: Some patients had more than 1 adverse reaction.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are no reports to date of acute toxicity associated with overdosage of pentamidine; consequently there is no specific information available on symptoms.

In general, overdosage of pentamidine would be expected to produce effects that are extensions of the common adverse reactions or of the serious metabolic sequelae observed (see Warnings and Precautions).

Available clinical pharmacology data suggest that a dose up to 40 times the recommended dose of inhaled pentamidine would be required to produce systemic levels similar to a single 4 mg/kg i.v. dose.

In case of suspected overdosage, treatment should be symptomatic and supportive.

Dosage And Administration: Inhalation: For prophylaxis of P. carinii pneumonia, pentamidine is administered as an aerosol via the Respirgard II nebulizer system, a continuous flow device that stores the drug during exhalations.

Adults: 300 mg once every 4 weeks.

Administration: The contents of one 300 mg vial should be dissolved in 6 mL of sterile water for injection. Place the entire reconstituted contents into the Respirgard II nebulizer reservoir.

The dose should be delivered until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 L/minute from a 40 to 50 pounds per square inch (PSI) air or oxygen source. Alternatively, a 40 to 50 PSI air compressor can be used with flow limited by setting the flowmeter at 5 to 7 L/minute or by setting the pressure at 22 to 25 PSI. Low pressure (less than 20 PSI) compressors should not be used.

When the nebulizer mouthpiece is firmly in the patient’s mouth, turn on the gas source. Instruct the patient to breathe only through the mouth, so that any exhaled drug or microorganisms will be trapped by the exhalation filter of the nebulizer.

The patient should be instructed to breathe at a normal rate, but also to take a deep breath at least once every minute by exhaling all of the air from the lungs and then inspiring deeply to refill them. If possible, the patient should hold his breath for a few seconds before exhaling.

Alternatives to this breathing pattern are: have the patient either lie in the supine position or take half of the therapy lying on either side.

If the patient feels a need to take a break, turn off the gas supply to the nebulizer for a few minutes until the patient feels able to resume therapy.

The Respirgard II nebulizer should not be reused . Discard appropriately.

Environmental and occupational exposure: The following guidelines are recommended for administration of aerosolized pentamidine in order to reduce the risk of exposing health care providers to aerosolized pentamidine or potential respiratory infectious agents:

1. Use an approved aerosol generator that facilitates the delivery of a particle size of 1 to 2 microns. This not only ensures optimal aerosol deposition but also minimizes coughing caused by larger, more irritating particles.

2. Use a filter on the expiratory side of the aerosol generator to minimize the release of pentamidine into the treatment area.

3. Pretreatment of susceptible patients with a bronchodilator may help to minimize coughing.

4. Adequate ventilation (at least 6 airflow changes per hour) in the treatment area is desirable to minimize the possible presence of tuberculosis organisms and to dispel any particles of aerosolized pentamidine that may have been accidentally released into the room.

5. Optional use by care-givers of surgical face masks and close fitting protective eyewear may reduce the likelihood of side effects in the upper respiratory tract and the irritating conjunctivitis that may occur.

6. Patients should be evaluated for the presence of tuberculosis prior to initiating prophylaxis for PCP. Health care workers administering aerosolized pentamidine should be screened periodically for tuberculosis.

7. Care must be taken to ensure that the aerosol generator is activated only during actual treatments and is turned off when not in use.

8. Care must be taken during aerosol perparation to minimize contact with mucous membranes.

9. Pregnant and nursing health care workers may wish to avoid exposure to pentamidine.

10. It is recommended that all health care workers should practice so-called universal precautions with all patients all of the time.

Injection: For treatment of P. carinii pneumonia, pentamidine may be administered i.v. or i.m. When administered i.v., pentamidine must be given only by slow infusion (i.e. over a period of at least 60 minutes and preferably over a period of 2 to 3 hours). I.M. administration should be reserved for patients with adequate muscle mass and for whom a slow i.v. infusion is not practical. The i.m. administration of pentamidine is normally not recommended because of poor local tolerance (see Precautions).

Since severe hypotension reactions may occur, patients receiving pentamidine should be in a supine position and blood pressure should be closely monitored during administration of the drug and several times thereafter until blood pressure is stable.

Adults: The recommended regimen is 4 mg/kg once a day for 14 to 21 days. The benefits and risks of therapy for longer than 14 doses are not well defined.

Patients with Renal Failure (creatinine clearance less than 35 mL/min): Life-threatening infections: 4 mg/kg once daily for 7 to 10 days then 4 mg/kg on alternate days to complete the course of 14 doses. Less severe infections: 4 mg/kg on alternate days for 14 doses.

Children: Clinical and pharmacokinetic data are extremely limited and further investigation is necessary to fully characterize the pharmacokinetics of pentamidine in this age group. However, a dosage of 4 mg/kg has been used in children. Pentamidine should be considered only if there is no other alternate treatment available.

Administration: I.V. infusion: The further diluted solution should be administered over a period of at least 60 minutes and preferably over a period of 2 to 3 hours.

I.M. injection: The appropriate volume of reconstituted solution should be administered well within the body of a relatively large muscle mass.

Reconstitution: For Inhalation: The contents of 1 vial (300 mg) must be dissolved with 6 mL of sterile water for injection.

Incompatibilities: Do not use saline solution for reconstitution because the drug may precipitate. Do not mix the solution with any other drugs.

Stability and Storage: Store unreconstituted powder at room temperature and protect from light. Reconstituted powder should be used immediately and not stored for later use.

Further dilute the appropriate volume of reconstituted solution with 50 to 500 mL of a 5% dextrose or 0.9% sodium chloride solution. Reconstituted pentamidine should not be mixed with any other injection solution. These are single dose vials; discard the unused portions.

Stability and Storage: Reconstituted solutions that have been further diluted in 5% dextrose solution to a concentration of approximately 2 mg/mL are stable for up to 24 hours at room temperature. Store unreconstituted powder at room temperature and protect from light.

For I.M. Injection: Reconstitute only with Sterile Water for Injection as for i.v. injection but do not further dilute.

Incompatibilities: After reconstitution but prior to parenteral administration, pentamidine should not be mixed with any injection solution other than 5% dextrose and 0.9% sodium chloride injections.

Availability And Storage: 200 mg: Each vial of sterile powder for injection after reconstitution contains: pentamidine isethionate 200 mg. Nonmedicinal ingredients: none. Boxes of 5.

300 mg: Each vial of sterile powder for injection after reconstitution contains: pentamidine isethionate 300 mg. Nonmedicinal ingredients: none. Boxes of 5.

Store at room temperature. Protect from light.

PENTACARINAT® Rhône-Poulenc Rorer Pentamidine Isethionate Antiparasitic Agent

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