Pyramide

Uses

Pyramide is used for the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.

• The current recommendation of the CDC for drug-susceptible disease is to use a six-month regimen for initial treatment of active tuberculosis, consisting of isoniazid, rifampin and Pyramide given for 2 months, followed by isoniazid and rifampin for 4 months
• Patients with drug-resistant disease should be treated with regimens individualized to their situation. Pyramide frequently will be an important component of such therapy.
• In patients with concomitant HIV infection, the physician should be aware of current recommendation of CDC. It is possible these patients may require a longer course of treatment

It is also used after treatment failure with other primary drugs in any form of active tuberculosis.

Pyramide should only be used in conjunction with other effective antituberculous agents.

Pyramide is also used to associated treatment for these conditions: Active Tuberculosis, Pulmonary Tuberculosis (TB)

How Pyramide works

Pyramide diffuses into active M. tuberculosis that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyramide and its analogs inhibited the activity of purified FAS I.

It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.

Dosage

Pyramide dosage

Usual Adult Dose for Tuberculosis: Active:

15 to 30 mg/kg (up to 2 g) orally once a day in combination with three other antituberculous drugs for the initial 2 months of a 6-month or 9-month treatment regimen, until drug susceptibility tests are known. An alternate dosing regimen of 50 to 75 mg/kg (up to 3 g) orally twice a week may be used after 2 weeks of daily therapy to increase patient compliance.

Alternatively, the CDC, The American Thoracic Society, and the Infectious Diseases Society of America suggest the following dosing based on estimated lean body weight:

Daily dosing:

• 40 to 45 kg: 1000 mg
• 56 to 75 kg: 1500 mg
• 76 to 90 kg: 2000 mg

Twice weekly dosing:

• 40 to 55 kg: 2000 mg
• 56 to 75 kg: 3000 mg
• 76 to 90 kg: 4000 mg

Thrice weekly dosing:

• 40 to 55 kg: 1500 mg
• 56 to 75 kg: 2500 mg
• 76 to 90 kg: 3000 mg

Usual Adult Dose for Tuberculosis: Latent:

A public health expert should be consulted prior to the use of the combination regimen with rifampin.

15 to 20 mg/kg, based on actual body weight (lean), orally once daily (maximum 2 g) for 2 months. Alternatively, a dosage of 50 mg/kg may be administered orally twice-weekly (maximum 4 g).

Usual Pediatric Dose for Tuberculosis: Active:

(Used as part of a multidrug regimen. Treatment regimens consist of an initial 2-month phase, followed by a continuation phase of 4 or 7 additional months. Frequency of dosing may differ depending on phase of therapy)

Infants, Children less than 40 kg and Adolescents 14 years and younger and less than 40 kg:Non-HIV patients:

• Daily therapy: 15 to 30 mg/kg/dose (maximum: 2 g/dose) once daily
• Directly observed therapy (DOT): 50 mg/kg/dose (maximum: 2 g/dose) twice weekly

HIV-exposed/infected patients:

• Daily therapy: 20 to 40 mg/kg/dose once daily (maximum: 2 g/day)

Side Effects

General: Fever, porphyria and dysuria have rarely been reported. Gout.

Gastrointestinal: The principal adverse effect is a hepatic reaction. Hepatotoxicity appears to be dose related, and may appear at any time during therapy. GI disturbances including nausea, vomiting and anorexia have also been reported.

Hematologic and Lymphatic: Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum iron concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported.

Other: Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritis have been reported. Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely.

Toxicity

Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.

Precaution

Pyramide is contraindicated in patients with severe hepatic disease and with acute gout.

Patients started on pyrazinamide should have baseline serum uric acid and liver function test results. Liver function should be monitored closely during therapy. Patients with preexisting liver disease or those at increased risk of drug related hepatitis should be monitored closely.

Pyramide should be discontinued and not restarted if signs of hepatocellular damage or hyperuricemia with an acute gouty arthritis appear.

Polyarthralgias have been reported in patients. The pain may respond to aspirin or other nonsteroidal anti-inflammatory agents.

Caution should be used in patients with a history of diabetes mellitus, as management of the disease may be more difficult.

Primary resistance of Mycobacterium tuberculosis to pyrazinamide is not common. In cases with known or suspected drug resistance, in vitro susceptibility tests with recent cultures of Mycobacterium tuberculosis against pyrazinamide and the usual primary drugs should be conducted. There are few reliable in vitro tests for pyrazinamide resistance. A reference laboratory capable of performing these tests must be utilized.

Clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased renal or hepatic function, and of concomitant disease or other drug therapy.

Interaction

Antagonises the effect of uricosuric agents (e.g. probenecid, sulfinpyrazone). May reduce the contraceptive effect of oestrogens. May inactivate oral typhoid vaccine. May increase the serum concentration of ciclosporin. May enhance the hepatotoxic effect of rifampicin.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Pyramide Drug Interaction

Unknown: aspirin, antihemophilic factor, ipratropium, amoxicillin / clavulanate, entecavir, sulfamethoxazole / trimethoprim, ivacaftor, multivitamin with minerals, acetaminophen, montelukast, tramadol, valproic acid, multivitamin, thiamine, cyanocobalamin, riboflavin, pyridoxine, ascorbic acid, cholecalciferol, phytonadione

Pyramide Disease Interaction

Major: gout, hepatotoxicity, liver disease, renal dysfunctionModerate: diabetes mellitus, hemodialysis

Elimination Route

Rapidly and well absorbed from the gastrointestinal tract.

Half Life

9-10 hours (normal conditions)

Elimination Route

Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours

Pregnancy & Breastfeeding use

Pregnancy Category C. Animal reproduction studies have not been conducted with Pyramide. It is also not known whether Pyramide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pyramide should be given to a pregnant woman only if clearly needed.

Nursing Mothers: Pyramide has been found in small amounts in breast milk. Therefore, it is advised that Pyramide be used with caution in nursing mothers taking into account the risk-benefit of this therapy.

Contraindication

Pyramide is contraindicated in persons:

• With severe hepatic damage.
• Who have shown hypersensitivity to it.
• With acute gout.

Special Warning

Usage in Children: Pyramide regimens employed in adults are probably equally effective in children. Pyramide appears to be well tolerated in children.

Geriatric Use: Clinical studies of Pyramide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 or renal function, and of concomitant disease or other drug therapy.It does not appear that patients with impaired renal function require a reduction in dose. It may be prudent to select doses at the low end of the dosing range, however.

Renal Dose Adjustments: The manufacturer recommends to start therapy at low end of dosage range and monitor patient closely.For the treatment of active tuberculosis, the CDC, ATS, and IDSA recommend against daily dosing. For patients with CrCl less than 30 mL/min or patients receiving hemodialysis the recommended dose is 25 to 35 mg/kg per dose three times per week.

Liver Dose Adjustments: Monitor patients closely.

Dose Adjustments: 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 or renal function, and of concomitant disease or other drug therapy.

If organism is susceptible to isoniazid and rifampin, pyrazinamide is continued for the first 2 months of a 6-month course of therapy (9-months if HIV positive). If primary drug resistance is shown, drug regimens should be adjusted as needed and continued for at least 6 months, or 3 months beyond culture conversion (9 months, or 6 months beyond culture conversion if HIV positive). If multiple-drug resistance is demonstrated, therapy should be continued for 12 to 24 months following culture conversion.

Acute Overdose

Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyramide is dialyzable.

Storage Condition

Store between 15-30° C.

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