Overdosage with Pentomer 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 Pentomer 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 Pentomer in patients who have overdosed.
Pentomer 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.
Clinical trials were conducted using either extended-release Pentomer tablets for up to 60 weeks or immediate-release Pentomer 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 Pentomer tablets, immediate-release Pentomer 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
| (Number of Patients at Risk) | Extended-Release Tables | Immediate-Release Caps ules | ||
| Commercially Available | Used Only For Controlled Clinical Trials | |||
| Pentomer (321) | Placebo (128) | Pentomer (177) | Placebo (138) | |
| Discontinued for Side Effect | 3.1 | 0 | 9.6 | 7.2 |
| CARDIOVASCULAR SYSTEM | ||||
| Angina/Chest Pain | 0.3 | - | 1.1 | 2.2 |
| Arrhythmia/Palpitation | - | - | 1.7 | 0.7 |
| Flushing | - | - | 2.3 | 0.7 |
| DIGESTIVE SYSTEM | ||||
| Abdominal Discomfort | - | - | 4.0 | 1.4 |
| Belching/Flatus/Bloating | 0.6 | - | 9.0 | 3.6 |
| Diarrhea | - | - | 3.4 | 2.9 |
| Dyspepsia | 2.8 | 4.7 | 9.6 | 2.9 |
| Nausea | 2.2 | 0.8 | 28.8 | 8.7 |
| Vomiting | 1.2 | - | 4.5 | 0.7 |
| NERVOUS SYSTEM | ||||
| Agitation/Nervousness | - | - | 1.7 | 0.7 |
| Dizziness | 1.9 | 3.1 | 11.9 | 4.3 |
| Drowsiness | - | - | 1.1 | 5.8 |
| Headache | 1.2 | 1.6 | 6.2 | 5.8 |
| Insomnia | - | - | 2.3 | 2.2 |
| Tremor | 0.3 | 0.8 | - | - |
| Blurred Vision | - | - | 2.3 | 1.4 |
Pentomer 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 Pentomer 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.
Pentomer extended-release tablets are indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. Pentomer 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.
No information provided.
PRECAUTIONS GeneralAt the first sign of anaphylactic/anaphylactoid reaction, Pentomer must be discontinued.
Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Pentomer 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 Pentomer 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 Pentomer 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 FertilityLong-term studies of the carcinogenic potential of Pentomer 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. Pentomer 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.
PregnancyCategory 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. Pentomer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing MothersPentomer and its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for Pentomer 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 UseSafety and effectiveness in pediatric patients have not been established.
Geriatric UseClinical studies of Pentomer 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.
The usual dosage of Pentomer in extended-release tablet form is one tablet (400 mg) three times a day with meals.
While the effect of Pentomer 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 Pentomer 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.
