Polfilin ret.

Polfilin ret. extended-release tablets are indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. Polfilin ret. can improve function and symptoms but is not intended to replace more definitive therapy, such as surgical bypass, or removal of arterial obstructions when treating peripheral vascular disease.

Polfilin ret. 400 is indicated in the treatment of peripheral vascular disease, including intermittent claudication and rest pain.

Clinical Use

Trental® (pentoxifylline) is indicated for the symptomatic treatment of:

• patients with chronic occlusive peripheral vascular disorders of the extremities;

In such patients Trental may give relief of signs and symptoms of impaired blood flow, such as intermittent claudication or trophic ulcers.

The usual dosage of Polfilin ret. in extended-release tablet form is one tablet (400 mg) three times a day with meals.

While the effect of Polfilin ret. may be seen within 2 to 4 weeks, it is recommended that treatment be continued for at least 8 weeks. Efficacy has been demonstrated in double-blind clinical studies of 6 months duration.

Digestive and central nervous system side effects are dose related. If patients develop these effects it is recommended that the dosage be lowered to one tablet twice a day (800 mg/day). If side effects persist at this lower dosage, the administration of Polfilin ret. should be discontinued.

In patients with severe renal impairment (creatinine clearance below 30 mL/min) reduce dose to 400 mg once a day.

Dosing information cannot be provided for patients with hepatic impairment.

The recommended initial dose is 1 tablet (400 mg) three times daily; two tablets daily may prove sufficient in some patients, particularly for maintenance therapy. Tablets should be taken with or immediately after meals, and swallowed whole with plenty of water.

Special Cases: In patients with impairment of renal function (creatinine clearance below 30ml/min) a dose reduction by approximately 30% to 50% may be necessary guided by individual tolerance.

Recommended Dose and Dosage Adjustment

The recommended starting dosage of Trental (pentoxifylline) is 400 mg twice daily after meals. The usual dose is 400 mg twice or three times daily. A maximum of 400 mg three times daily should not be exceeded.

It may take up to two months to obtain full results.

Polfilin ret. mg sustained release tablets must be swallowed whole.

Polfilin ret. should not be used in patients with recent cerebral and/or retinal hemorrhage or in patients who have previously exhibited intolerance to this product or methylxanthines such as caffeine, theophylline, and theobromine.

Polfilin ret. 400 is contra-indicated in cases where there is known hypersensitivity to the active constituent, pentoxifylline other methyl xanthines or any of the excipients. Also in patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction and severe cardiac arrhythmias.

The use of Trental (pentoxifylline) is contraindicated in:

• Patients who are hypersensitive to pentoxifylline or other xanthines such as caffeine, theophylline and theobromine or to any ingredient in the formulation or component of the container (see Dosage Forms, Composition and Packaging).
• Patients with acute myocardial infraction;
• Patients with severe coronary artery disease when, in the physician's judgement, myocardial stimulation might prove harmful;
• Patients with hemorrhage (e.g. extensive retinal bleeding) or at risk of increased bleeding;
• Patients with peptic ulcers or recent history thereof.

WARNINGS

No information provided.

PRECAUTIONS

General

At the first sign of anaphylactic/anaphylactoid reaction, Polfilin ret. must be discontinued.

Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Polfilin ret. has been used safely for treatment of peripheral arterial disease in patients with concurrent coronary artery and cerebrovascular diseases, but there have been occasional reports of angina, hypotension, and arrhythmia. Controlled trials do not show that Polfilin ret. causes such adverse effects more often than placebo, but, as it is a methylxanthine derivative, it is possible some individuals will experience such responses. Patients on warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration, cerebral and/or retinal bleeding) should have periodic examinations for bleeding including, hematocrit and/or hemoglobin.

In patients with hepatic or renal impairment, the exposure to Polfilin ret. and/or active metabolites is increased. The consequences of the increase in drug exposure are not known (see Pharmacokinetics and Metabolism and DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis And Impairment Of Fertility

Long-term studies of the carcinogenic potential of Polfilin ret. were conducted in mice and rats by dietary administration of the drug at doses up to 450 mg/kg (approximately 19 times the maximum recommended human daily dose (MRHD) in both species when based on body weight; 1.5 times the MRHD in the mouse and 3.3 times the MRHD in the rat when based on body surface area). In mice, the drug was administered for 18 months, whereas in rats, the drug was administered for 18 months followed by an additional 6 months without drug exposure. In the rat study, there was a statistically significant increase in benign mammary fibroadenomas in females of the 450 mg/kg group. The relevance of this finding to human use is uncertain. Polfilin ret. was devoid of mutagenic activity in various strains of Salmonella (Ames test) and in cultured mammalian cells (unscheduled DNA synthesis test) when tested in the presence and absence of metabolic activation. It was also negative in the in vivo mouse micronucleus test.

Pregnancy

Category C.

Teratogenicity studies have been performed in rats and rabbits using oral doses up to 576 and 264 mg/kg, respectively. On a weight basis, these doses are 24 and 11 times the maximum recommended human daily dose (MRHD); on a body-surface-area basis, they are 4.2 and 3.5 times the MRHD. No evidence of fetal malformation was observed. Increased resorption was seen in rats of the 576 mg/kg group. There are no adequate and well controlled studies in pregnant women. Polfilin ret. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Polfilin ret. and its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for Polfilin ret. in rats, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Polfilin ret. did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The active metabolite V is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

At the first signs of an anaphylactic/anaphylactoid reaction, Polfilin ret. 400 must be discontinued immediately, and a physician must be informed.

Particular careful monitoring is required:

In patients with hypotension or severe coronary artery disease, Polfilin ret. 400 should be used with caution, as a transient hypotensive effect is possible and, in isolated cases, might result in a reduction in coronary artery perfusion.

Particularly careful monitoring is required in patients with impaired renal function.).

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WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

General

At the first signs of an anaphylactic/anaphylactoid reaction, Trental must be discontinued and a physician must be informed.

Patients with hepatic impairment should be closely monitored during Trental therapy and may require lower doses. Since Trental (pentoxifylline) is extensively metabolized in the liver, the use of this drug is not recommended in patients with severe hepatic impairment of liver function (Child-Pugh class C, score > 9).

Patients with renal impairment (creatinine clearance below 80 mL/min) should be closely monitored during Trental therapy and may require lower doses. Since Trental (pentoxifylline) is eliminated through the kidneys, the use of this drug is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL/min).

Cardiovascular

Low, labile blood pressure

Caution should be exercised when administering Trental (pentoxifylline) to patients with low or labile blood pressure. In such patients any dose increase should be done gradually and careful monitoring is required.

Patients with severe cardiac arrhythmias should be closely monitored during Trental therapy.

Hematologic

The administration of Trental has been associated with bleeding and/or prolonged prothrombin time (see DRUG INTERACTIONS). The risk of bleeding may be increased by combined treatment with anticoagulant agents or use in coagulation disorders. Therefore, in patients with coagulation disorders or being treated with anticoagulant therapy, Trental should be used with caution and only, when in the physician's judgement, the potential benefit outweighs the risk. Careful monitoring is required.

Special Populations

Pregnant Women

Reproduction studies have been performed in rats, mice and rabbits at doses up 23, 2 and 11 times the maximum recommended daily human dose and have revealed no evidence of impaired fertility or harm to the fetus due to pentoxifylline. The drug has been shown to cross the bloodplacenta barrier in mice. There is no adequate experience in pregnant women. Therefore, Trental is not recommended for women who are, or may become, pregnant unless the expected benefits for the mothers outweigh the potential risk to the fetus.

Nursing Women

Pentoxifylline and its major metabolites are excreted in human milk, following a 400 mg single oral dose of Trental. The patient should be advised to discontinue nursing or to discontinue taking the drug depending on the importance of the drug to the mother.

Pediatrics

The use of Trental in patients below the age of 18 years is not recommended as safety and effectiveness have not been established in this age group.

Geriatrics

Trental should be used with caution in elderly patients as peak plasma levels of pentoxifylline and its metabolites are moderately higher in this age group. Elderly patients had a slight increase in the incidence of some adverse effects. Careful dose adjustment is therefore recommended.

Clinical trials were conducted using either extended-release Polfilin ret. tablets for up to 60 weeks or immediate-release Polfilin ret. capsules for up to 24 weeks. Dosage ranges in the tablet studies were 400 mg bid to tid and in the capsule studies, 200 to 400 mg tid. The table summarizes the incidence (in percent) of adverse reactions considered drug related, as well as the numbers of patients who received extended-release Polfilin ret. tablets, immediate-release Polfilin ret. capsules, or the corresponding placebos. The incidence of adverse reactions was higher in the capsule studies (where dose related increases were seen in digestive and nervous system side effects) than in the tablet studies. Studies with the capsule include domestic experience, whereas studies with the extended-release tablets were conducted outside the U.S.

The table indicates that in the tablet studies few patients discontinued because of adverse effects.

INCIDENCE (%) OF SIDE EFFECTS

Polfilin ret. has been marketed in Europe and elsewhere since 1972. In addition to the above symptoms, the following have been reported spontaneously since marketing or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain:

Cardiovascular - dyspnea, edema, hypotension.

Digestive - anorexia, cholecystitis, constipation, dry mouth/thirst.

Nervous - anxiety, confusion, depression, seizures, aseptic meningitis.

Respiratory - epistaxis, flu-like symptoms, laryngitis, nasal congestion.

Skin and Appendages - brittle fingernails, pruritus, rash, urticaria, angioedema.

Special Senses - blurred vision, conjunctivitis, earache, scotoma.

Miscellaneous - bad taste, excessive salivation, leukopenia, malaise, sore throat/swollen neck glands, weight change.

A few rare events have been reported spontaneously worldwide since marketing in 1972. Although they occurred under circumstances in which a causal relationship with Polfilin ret. could not be established, they are listed to serve as information for physicians. Cardiovascular - angina, arrhythmia, tachycardia. Digestive - hepatitis, jaundice, cholestasis, increased liver enzymes; and Hemic and Lymphatic - decreased serum fibrinogen, pancytopenia, aplastic anemia, leukemia, purpura, thrombocytopenia. Immune system disorders - anaphylactic reaction, anaphylactoid reaction, anaphylactic shock.

These adverse reactions have been reported in clinical trials or post-marketing. Frequencies are unknown.

Description of selected adverse reactions

* Reports of aseptic meningitis were predominantly in patients with underlying connective tissue disorders

** A few very rare events of bleeding (e.g. skin, mucosa) have been reported in patients treated with Polfilin ret. with and without anticoagulants or platelet aggregation inhibitors. The serious cases are predominantly concentrated in the gastrointestinal, genitourinary, multiple site and surgical wound areas and are associated with bleeding risk factors. A causal relationship between Polfilin ret. therapy and bleeding has not been established. Thrombocytopenia has occurred in isolated cases.

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 professional are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The most frequent adverse event reported with Trental (pentoxifylline) is nausea (14%). Individual signs/symptoms listed in the table below occurred at an incidence between 1 and 3%, except when stated otherwise.

Less Common Clinical Trial Adverse Drug Reactions ( < 1%)

Body as a whole: Muscle aches/spasm, weight change, backache, bad taste in mouth, leg cramps, fever, weakness, sweating.

Cardiovascular: Chest pain, arrhythmia, hypertension, dyspnea, edema, hypotension, angina, tachycardia.

Central nervous system: Drowsiness/sleepiness, tremor, agitation anxiety, confusion, insomnia, restlessness.

Gastrointestinal: Abdominal burning, abdominal pain, anorexia flatus, constipation, haemorrhage, heartburn, salivation, dry mouth/throat, hepatitis, jaundice, increased liver enzymes.

Hemic and lymphatic: Decreased serum fibrinogen, pancytopenia, purpura, thrombocytopenia, leucopenia, anemia, aplastic anemia.

Hypersensitivity reactions: Pruritis, rash, urticaria, angioedema.

Organs of special sense: Blurred vision, scotoma, lacrimation, epistaxis.

Post-Market Adverse Drug Reactions

Hepatobiliary disorders: Intrahepatic cholestasis.

Immune system disorders: Severe anaphylactic/anaphylactoid reaction with, for example, angioneurotic edema, bronchospasms, sometimes shock.

Infections and infestations: Aseptic meningitis.

Investigations: Transaminase elevation.

Psychiatric: Sleep disturbances.

Skin and subcutaneous tissue disorders: Reddening of skin.

Vascular disorder: Haemorrhage

Overdosage with Polfilin ret. has been reported in pediatric patients and adults. Symptoms appear to be dose related. A report from a poison control center on 44 patients taking overdoses of entericcoated Polfilin ret. extended-release tablets noted that symptoms usually occurred 4 to 5 hours after ingestion and lasted about 12 hours. The highest amount ingested was 80 mg/kg; flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation occurred. All patients recovered. In addition to symptomatic treatment and gastric lavage, special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions. Activated charcoal has been used to absorb Polfilin ret. in patients who have overdosed.

The treatment of overdosage should be symptomatic with particular attention to supporting the cardiovascular system.

Overdosage with Trental (pentoxifylline) has been reported in children and adults. Symptoms appear to be dose related and usually occurred 4-5 hours after ingestion and lasted about 12 hours. Initial manifestations of acute overdose with pentoxifylline may be nausea, dizziness, tachycardia, fever, gastrointestinal bleeding – coffee-ground vomiting and areflexia. The highest amount ingested was 80 mg/kg with which flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation have been observed. All patients recovered.

No specific antidote is known. In addition to symptomatic treatment and gastric lavage, special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions with intravenous diazepam. Activated charcoal has been used to absorb pentoxifylline in patients who have overdosed.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

The half life of absorption of Polfilin ret. 400 is 4-6 hours. Pentoxifylline is extensively metabolised, mainly in the liver. Sixty percent of a single dose of Polfilin ret. 400 is eliminated via the kidney over 24 hours.

Pentoxifylline is almost completely absorbed after oral administration. The Polfilin ret. mg sustained release tablet showed an initial peak plasma pentoxifylline concentration 2 to 3 hours post-administration. The drug is extensively metabolized. The active main metabolite 1-(5- hydroxyhexyl)-3,7-dimethyl-xanthine (metabolite I) is measurable in twice the concentration in plasma of that of its parent substance. Biotransformation products are almost exclusively eliminated by the kidneys.

Food intake before the administration of Trental delayed the absorption but did not decrease it.