Panmitin

Uses

For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichiacoli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species and coagulase-negative Staphylococcus species, including S. saprophyticus.

Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to trimethoprim. Therapy may be initiated prior to obtaining the results of these tests.

Panmitin is also used to associated treatment for these conditions: Acute Exacerbation of Chronic Bronchitis (AECB) caused by susceptible bacteria, Acute Otitis Media caused by susceptible bacteria, Bacterial Conjunctivitis caused by susceptible bacteria, Blepharoconjunctivitis caused by susceptible bacteria, Brucellosis, Dysentery, Bacillary, Nocardiosis, Pneumocystis Jirovecii Pneumonia, Urinary Tract Infection caused by susceptible bacteria, Bacterial blepharitis caused by susceptible bacteria, Susceptible Cholera, Susceptible Enteritis infectious caused by Shigella flexneri, Susceptible Enteritis infectious caused by Shigella sonnei, Susceptible Travelers' Diarrhea caused by Enterotoxigenic E. Coli (ETEC) Infection, Uncomplicated Urinary Tract Infection caused by susceptible bacteria

How Panmitin works

Panmitin is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Panmitin binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes.

Panmitin is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity.

Dosage

Panmitin dosage

The usual oral adult dosage is 100 mg of trimethoprim every 12 hours or 200 mg trimethoprim every 24 hours, each for 10 days.

The use of trimethoprim in patients with acreatinineclearance of less than 15 ml/min is not recommended.

For patients with a creatinine clearance of 15 to 30 ml/min, the dose should be 50 mg every 12 hours

Side Effects

Pruritus, rash, urticaria, mild GI disturbance (e.g. nausea, vomiting, glossitis, sore mouth); disturbance of liver enzymes, photosensitivity, angioedema, myalgia, headache; hyperkalaemia, hyponatraemia; agranulocytosis. Rarely, fever, cholestatic jaundice, exfoliative dermatitis, anaphylaxis, aseptic meningitis, megaloblastic anaemia, thrombocytopenia, leucopenia, neutropenia, methaemoglobinaemia.

Toxicity

The oral LD₅₀ in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively.

Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit.

Precaution

Patient with actual or potential folate deficiency (e.g. malnourished, chronic anticonvulsant therapy, elderly). Hepatic and renal impairment. Childn (esp those with fragile X chromosome associated with mental retardation). Pregnancy and lactation.

Interaction

May increase concentration of dapsone. Increased elimination and shortened elimination half-life with rifampicin. Increases concentration of phenytoin, digoxin, procainamide, rosiglitazone, repaglinide, zidovudine, zalcitabine, lamivudine. Increased risk of nephrotoxicity with ciclosporin. Potentiates anticoagulant effect of warfarin. May cause hyponatraemia with diuretics. May cause megaloblastic anaemia with other folate inhibitors (e.g. pyrimethamine, methotrexate). May increase potential for bone marrow aplasia with bone barrow depressants. Increased risk of hyperkalaemia with ACE inhibitors.

Food Interaction

Panmitin Drug Interaction

Unknown: aspirin, duloxetine, apixaban, omega-3 polyunsaturated fatty acids, furosemide, atorvastatin, pregabalin, nitrofurantoin, metoprolol, metoprolol, polyethylene glycol 3350, esomeprazole, acetaminophen / hydrocodone, acetaminophen, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Panmitin Disease Interaction

Major: folate deficiencyModerate: dialysis, renal dysfunction

Volume of Distribution

Panmitin is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Panmitin distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Panmitin is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora.

Elimination Route

Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C_max) are achieved within 1 to 4 hours (T_max) following the administration of a single 100mg dose. Panmitin appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/L·h.

Half Life

Panmitin half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction.

Clearance

Following oral administration, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 mL/min.

Elimination Route

Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is unchanged parent drug.

Pregnancy & Breastfeeding use

Pregnancy Category C. Panmitin has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.

Nursing Mothers: Panmitin is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when trimethoprim is administered to a nursing woman.

Contraindication

Hypersensitivity. Blood dyscrasias (e.g. megaloblastic anaemia).

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of Panmitin as a single agent has not been established in pediatric patients under 12 years of age.

Geriatric Use: Clinical studies of Panmitin tablets 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 response 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.

Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published. Panmitin 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 potassium concentrations and to monitor renal function by calculating creatinine clearance.

Acute Overdose

Symptoms: Nausea, vomiting, dizziness, headache, mental depression, confusion, bone marrow depression (e.g. thrombocytopenia, leucopenia, megaloblastic anaemia).

Management: Symptomatic and supportive treatment. May employ gastric lavage and forced diuresis. Enhance elimination through urine acidification. May administer Ca folinate (5-15 mg daily) if bone marrow depression occurs.

Storage Condition

Store between 15-25˚C. Protect from light

Innovators Monograph

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