Zerit

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Zerit

Classes

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI)s

Administration
Oral Administration

May be administered without regard to meals.

Oral Liquid Formulations

Shake well prior to each administration.
Measure dosage with the manufacturer provided measuring cup.
 
Reconstitution:
Add 202 mL of purified water to the container to produce 200 mL (deliverable volume) of a 1 mg/mL solution
Shake container vigorously until powder dissolves completely; the solution may appear slightly hazy.
Storage: Store reconstituted solution in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F); discard any unused portion after 30 days.

Adverse Reactions
Severe

pancreatitis / Delayed / 0-1.0
hepatic failure / Delayed / 0-1.0
lactic acidosis / Delayed / 0-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
hepatotoxicity / Delayed / Incidence not known

Moderate

hyperbilirubinemia / Delayed / 0-68.0
peripheral neuropathy / Delayed / 52.0-52.0
hyperamylasemia / Delayed / 14.0-14.0
elevated hepatic enzymes / Delayed / 11.0-13.0
neutropenia / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
anemia / Delayed / 0-1.0
hepatomegaly / Delayed / 0-1.0
hepatitis / Delayed / 0-1.0
hyperglycemia / Delayed / 0-1.0
diabetes mellitus / Delayed / 0-1.0
dyspnea / Early / Incidence not known
steatosis / Delayed / Incidence not known
tachypnea / Early / Incidence not known
lipodystrophy / Delayed / Incidence not known

Mild

headache / Early / 54.0-54.0
diarrhea / Early / 50.0-50.0
rash / Early / 40.0-40.0
vomiting / Early / 39.0-39.0
nausea / Early / 39.0-39.0
fever / Early / 0-1.0
myalgia / Early / 0-1.0
chills / Rapid / 0-1.0
macrocytosis / Delayed / 0-1.0
abdominal pain / Early / 0-1.0
anorexia / Delayed / 0-1.0
weakness / Early / 0-1.0
insomnia / Early / 0-1.0
weight loss / Delayed / Incidence not known
fatigue / Early / Incidence not known

Boxed Warning
Pancreatitis

Cases of fatal and nonfatal pancreatitis have occurred in treatment-naive and treatment-experienced patients treated with antiretroviral regimens that included both stavudine and didanosine, regardless of the degree of immunosuppression. Due to the increased risk for toxicity, concurrent treatment with stavudine and didanosine is contraindicated. If pancreatitis is suspected, treatment with stavudine and any other mediation that may be toxic to the pancreas should be suspended. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close monitoring.

Alcoholism, females, hepatic disease, hepatotoxicity or lactic acidosis, obesity

Stavudine should be used with caution in patients with known risk factors for hepatic disease. Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of stavudine. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, cohort and longitudinal studies suggest that this infrequent adverse event may be more often associated with antiretroviral regimens containing stavudine. A majority of these cases occurred in females. It is unknown if pregnant women are at increased risk; however, fatal cases of lactic acidosis, two with and one without pancreatitis, have occurred in women who were either pregnant or postpartum and whose antiretroviral therapy during gestation included stavudine and didanosine. Two of the infants of these women died. Clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Alcoholism, obesity, and prolonged exposure to nucleosides may also be risk factors for hepatotoxicity. However, hepatotoxicity has been reported in patients with no risk factors. In addition, deaths attributed to hepatotoxicity have occurred in patients receiving the combination of stavudine, didanosine, and hydroxyurea. Due to increased risk for toxicity, concurrent treatment of stavudine and didanosine is contraindicated, and use of stavudine and hydroxyurea should be avoided. Patients should be closely monitored for signs of liver toxicity during stavudine therapy. Treatment with stavudine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked elevation of hepatic enzymes. Permanent discontinuation of stavudine should be consider for patients with confirmed lactic acidosis.

Common Brand Names

Zerit

Dea Class

Rx

Description

Nucleoside reverse transcriptase inhibitor (NRTI)
Used for treatment of HIV infection in combination with other antiretroviral agents
Associated with higher incidence of lactic acidosis with hepatic steatosis than other NRTIs

Dosage And Indications
For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents. Oral dosage (immediate release capsules or oral solution) Adults weighing 60 kg or more

40 mg PO every 12 hours is the FDA-approved dosage and recommended by HIV guidelines. 30 mg PO every 12 hours is recommended by WHO guidelines.

Adults weighing 30 to 59 kg

30 mg PO every 12 hours.

Children and Adolescents weighing 60 kg or more

40 mg PO every 12 hours is the FDA-approved dosage and recommended by HIV guidelines. 30 mg PO every 12 hours is recommended by WHO guidelines.

Children and Adolescents weighing 30 to 59 kg

30 mg PO every 12 hours.

Infants and Children weighing less than 30 kg

1 mg/kg/dose PO every 12 hours.

Neonates 14 to 29 days

1 mg/kg/dose PO every 12 hours.

Neonates 0 to 13 days

0.5 mg/kg/dose PO every 12 hours.

Dosing Considerations
Hepatic Impairment

No dosage adjustment is required.

Renal Impairment

FDA-approved recommendations in adults: 
CrCl greater than 50 mL/min: No dosage adjustment needed.
CrCl 26 to 50 mL/min: Reduce recommended dose by 50% and give every 12 hours.
CrCl 10 to 25 mL/min: Reduce recommended dose by 50% and extend dosing interval to every 24 hours.
 
Other recommendations in adults:
GFR greater than 50 mL/min: No dosage adjustment needed.
GFR 10 to 50 mL/min: Reduce recommended dose by 50% and give every 12 to 24 hours.
GFR less than 10 mL/min: Reduce recommended dose by 50% and give every 24 hours.
 
Dosing recommendations in pediatric patients:
GFR greater than 50 mL/min/1.73m2: No dosage adjustment needed.
GFR 30 to 50 mL/min/1.73m2: Reduce recommended dose by 50% and give every 12 hours.
GFR less than or equal to 29 mL/min/1.73m2: Reduce recommended dose by 75% and give every 24 hours.
 
Intermittent hemodialysis
For adult patients, reduce recommended dose by 50% and give every 24 hours, administering after the completion of hemodialysis on dialysis days. For pediatric patients, reduce the recommended dose by 75% and give every 24 hours and administer after dialysis on dialysis days.
 
Peritoneal dialysis
No data are available in adult patients. For pediatric patients, reduce the recommended dose by 75% and give every 24 hours.
 
Continuos renal replacement therapy (CRRT)
No dosage adjustment needed in adult patients. For pediatric patients, reduce the recommended dose by 50% and give every 12 hours.

Drug Interactions

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Contraindicated) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed.
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like stavudine; the risk of peripheral neuropathy may be additive.
Didanosine, ddI: (Contraindicated) Concurrent administration of stavudine and didanosine is contraindicated. Use of these drugs together increases the risk for serious and life-threatening adverse events, including pancreatitis, lactic acidosis, hepatotoxicity, and peripheral neuropathy.
Doxorubicin Liposomal: (Moderate) It appears that doxorubicin inhibits the phosphorylation of stavudine in vitro. The clinical significance of this in vitro data is unknown and, therefore, concomitant use of stavudine and doxorubicin should be undertaken with caution.
Doxorubicin: (Moderate) It appears that doxorubicin inhibits the phosphorylation of stavudine in vitro. The clinical significance of this in vitro data is unknown and, therefore, concomitant use of stavudine and doxorubicin should be undertaken with caution.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Hydroxyurea: (Major) It is recommended that hydroxyurea not be used in patients with HIV; reports of hydroxyurea's improvement of viral suppression are inconsistent and hydroxyurea is associated with decreased CD4 counts. While there have been reports that hydroxyurea may enhance the antiretroviral activity of stavudine, the overall results of these reports are inconsistent, and the combined use of these drugs is associated with an increased incidence of stavudine-associated adverse effects, including pancreatitis and peripheral neuropathy. Additionally, there are postmarketing reports of hepatotoxicity and hepatic failure resulting in death with a treatment regimen of hydroxyurea and stavudine.
Interferons: (Major) Patients receiving stavudine with interferons (with or without ribavirin) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine, 3TC; Zidovudine, ZDV: (Contraindicated) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed.
Methadone: (Minor) Methadone decreases the bioavailability stavudine, d4T by slowing its absorption and increasing its first-pass metabolism. As a result, stavudine's AUC and Cmax are decreased by 18% and 39%, respectively; however, these effects are probably not clinically significant.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Probenecid: (Minor) Stavudine undergoes active tubular secretion, and renal elimination may be affected by probenecid, a drug known to interfere with tubular secretion. Resultant increases in serum levels can lead to toxicity.
Probenecid; Colchicine: (Minor) Stavudine undergoes active tubular secretion, and renal elimination may be affected by probenecid, a drug known to interfere with tubular secretion. Resultant increases in serum levels can lead to toxicity.
Ribavirin: (Moderate) Use stavudine with ribavirin and interferon together with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of stavudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Zidovudine, ZDV: (Contraindicated) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed.

How Supplied

Stavudine/Zerit Oral Cap: 15mg, 20mg, 30mg, 40mg
Stavudine/Zerit Oral Pwd F/Recon: 1mg, 1mL

Maximum Dosage
Adults

Greater than to equal to 60 kg: 80 mg/day PO.
Less than 60 kg: 60 mg/day PO.

Geriatric

Greater than or equal to 60 kg: 80 mg/day PO.
Less than 60 kg: 60 mg/day PO.

Adolescents

Greater than or equal to 60 kg: 80 mg/day PO.
30 kg to less than 60 kg: 60 mg/day PO.
Less than 30 kg: 2 mg/kg/day PO.

Children

Greater than or equal to 60 kg: 80 mg/day PO.
30 kg to less than 60 kg: 60 mg/day PO.
Less than 30 kg: 2 mg/kg/day PO.

Infants

2 mg/kg/day PO oral solution.

Neonates

Greater than or equal to 14 days: 2 mg/kg/day PO oral solution.
Less than 14 days: 1 mg/kg/day PO oral solution.

Mechanism Of Action

Stavudine inhibits the replication of retroviruses. In vitro studies show it inhibits replication of HIV in human cells. Antiretroviral activity is dependent on phosphorylation by cellular kinases to stavudine triphosphate. Once in the active form, stavudine inhibits HIV reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate and by its incorporation into viral DNA causing a termination of DNA elongation. Stavudine inhibits DNA elongation because it lacks an essential 3'-OH group. Stavudine triphosphate also inhibits cellular DNA polymerase beta and gamma and reduces the synthesis of mitochondrial DNA. Some resistance, including cross-resistance to zidovudine and didanosine, has been demonstrated in in vitro studies. Prolonged treatment can select and/or maintain thymidine analogue mutations that are associated with zidovudine resistance. Use should be avoided in the presence of thymidine analogue mutations.

Pharmacokinetics

Stavudine is administered orally. Stavudine distributes equally between red blood cells and plasma. Stavudine crosses the blood-brain barrier and distributes into the cerebrospinal fluid. Protein binding is negligible. The volume of distribution is 46 +/- 21 L.
 
Metabolism plays a limited role in stavudine clearance. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine. Approximately 95% of a radiolabeled dose was recovered in the urine, with 73.7% recovered as parent drug. Approximately 3% of the radiolabeled dose was recovered in the feces, with 62% recovered as parent drug. Body clearance of the drug is independent of dose, regardless of the route of administration. Terminal half-life following oral administration is roughly 2.3 hours in adults after a single oral dose. The mean elimination half-life after an IV dose is 1.15 +/- 0.35 hour and the mean elimination half-life after an oral dose is 1.6 +/- 0.23 hour. Excretion is about 40% renal via active tubular secretion and glomerular filtration.

Oral Route

Stavudine is rapidly absorbed following oral administration. Systemic exposure is the same regardless of capsule or solution administration. Mean absolute bioavailability is 86.4% +/- 18.2. Bioavailability increases proportionally to dosage, with peak concentrations occurring within 1 hour. In adults with HIV, the steady-state AUC is 2,568 +/- 454 ng x hour/mL, the steady-state Cmax is 536 +/- 146 ng/mL, and the steady-state Cmin is 8 +/- 9 ng/mL. Peak serum concentration is decreased by approximately 45% if the drug is administered with food, but total bioavailability remains unchanged.

Pregnancy And Lactation
Pregnancy

Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Stavudine is not recommended as part of an antiretroviral regimen in pregnant patients due to an increased risk of serious toxicity. If a patient becomes pregnant while taking stavudine, consider switching to an alternative treatment regimen. Available data from the Antiretroviral Pregnancy Registry (APR), which includes over 810 first trimester exposures to stavudine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When stavudine exposure occurred in the first trimester, prevalence of defects was 2.6% (95% CI: 1.6 to 3.9). Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Cases of lactic acidosis, some fatal, have been reported in pregnant patients receiving didanosine and stavudine together; concurrent use of these antiretroviral agents is contraindicated. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to stavudine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.

HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission; thus, replacement feeding is recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). Stavudine is excreted in human breast milk; the ratio of drug concentrations in breast milk to those found in maternal plasma is 1 to 1.76. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.