IRBESARTAN by Alembic Pharmaceuticals Inc. / Alembic Pharmaceuticals Limited IRBESARTAN tablet

IRBESARTAN by

Drug Labeling and Warnings

IRBESARTAN by is a Prescription medication manufactured, distributed, or labeled by Alembic Pharmaceuticals Inc., Alembic Pharmaceuticals Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: FETAL TOXICITY

       When pregnancy is detected, discontinue Irbesartan Tablets as soon as possible.
       Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)].

  • 1 INDICATIONS AND  USAGE

    1.1 Hypertension

    Irbesartan Tablets USP are  indicated  for  the  treatment  of  hypertension,  to  lower  blood  pressure.  Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events,  primarily strokes and myocardial infarction. These benefits have been seen in controlled trials  of antihypertensive drugs from a wide variety of pharmacologic classes including this  drug.


    Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).


    Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.


    Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

    Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.


    Irbesartan Tablets USP may be used alone or in combination with other antihypertensive agents.

    1.2 Nephropathy in Type 2 Diabetic Patients

    Irbesartan Tablets USP are indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). In this population, Irbesartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see Clinical Studies (14.2)].

  • 2 DOSAGE  AND  ADMINISTRATION

    2.1 General Considerations

    Irbesartan Tablets may be administered with other antihypertensive agents and with or without food.

    2.2 Hypertension

    The recommended initial dose of Irbesartan Tablet is 150 mg once daily. The dosage can be increased to a maximum dose of 300 mg once daily as needed to control blood pressure [see Clinical Studies (14.1)].

    2.3 Nephropathy in Type 2 Diabetic Patients

    The recommended dose is 300 mg once daily [see Clinical Studies (14.2)].

    2.4 Dose Adjustment in Volume and Salt-Depleted Patients

    The recommended initial dose is 75 mg once daily in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis) [see Warnings and Precautions (5.2)].

  • 3 DOSAGE FORMS  AND  STRENGTHS

    Irbesartan Tablets  75 mg are available as white to off white, oval shaped, biconvex, uncoated tablet, debossed with “L131” on one side and “75” on other side.


    Irbesartan Tablets  150 mg are available as white to off white, oval shaped, biconvex, uncoated tablet, debossed with “L132” on one side and “150” on other side.


    Irbesartan Tablets  300 mg are available as white to off white, oval shaped, biconvex, uncoated tablet, debossed with “L133” on one side and “300” on other side.

  • 4 CONTRAINDICATIONS

    Irbesartan Tablets are contraindicated in patients who are hypersensitive to any component of this product.

    Do not coadminister aliskiren with Irbesartan Tablets in patients with  diabetes.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Fetal Toxicity

    Use  of  drugs  that  act  on  the  renin-angiotensin  system  during  the  second  and  third  trimesters  of pregnancy  reduces  fetal  renal  function  and  increases  fetal  and  neonatal  morbidity  and  death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and  skeletal  deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,  hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan Tablets as soon as  possible [see Use in Specific Populations  (8.1)].

     

    5.2 Hypotension in Volume or Salt-Depleted Patients

    In patients with an activated renin-angiotensin system, such as volume or salt-depleted  patients (e.g. those being treated with high doses of diuretics), symptomatic hypotension may occur  after initialization of treatment with Irbesartan Tablets. Correct volume or salt depletion prior  to administration of Irbesartan Tablets or use a lower starting dose [see Dosage and Administration  (2.4)].

    5.3 Impaired Renal Function

    Changes  in  renal  function  including  acute  renal  failure  can  be  caused  by  drugs  that  inhibit  the renin-angiotensin system. Patients whose renal function may depend in part on the activity of  the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease,  severe heart  failure,  or  volume  depletion)  may  be  at  particular  risk  of  developing  acute  renal  failure  or death on Irbesartan Tablets. Monitor renal function periodically in these patients. Consider   withholding or discontinuing therapy in patients who develop a clinically significant decrease in  renal function on Irbesartan Tablets [see Drug Interactions  (7.3)].

  • 6 ADVERSE REACTIONS

    The following important adverse reactions are described elsewhere in the labeling:
       Hypotension in Volume or Salt-Depleted Patients [see Warnings and Precautions (5.2)]
       Impaired Renal Function [see Warnings and Precautions (5.3)]

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction  rates  observed  in  the  clinical  trials  of  a  drug  cannot  be  directly  compared  to  rates  in  the  clinical  trials of another drug and may not reflect the rates observed in practice. The adverse  reaction information from clinical trials does, however, provide a basis for identifying the adverse  events that appear to be related to drug use and for approximating  rates.

    Hypertension 

    Irbesartan Tablets have been evaluated for safety in more than 4300 patients with hypertension and  about 5000 subjects overall. This experience includes 1303 patients treated for over 6 months and  407 patients for 1 year or  more.


    In placebo-controlled clinical trials, the following adverse reactions were reported in at least  1% of  patients  treated  with  Irbesartan Tablets  (n=1965)  and  at  a  higher  incidence  versus  placebo  (n=641), excluding those too general to be informative and those not reasonably associated with the use  of drug  because  they  were  associated  with  the  condition  being  treated  or  are  very  common  in  the treated  population,  include:  diarrhea  (3%  vs  2%),  dyspepsia/heartburn  (2%  vs  1%),  and  fatigue (4% vs  3%).

     Irbesartan use was not associated with an increased incidence of dry cough, as is  typically associated  with  ACE  inhibitor  use.   In  placebo-controlled  studies,  the  incidence  of  cough  in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving  placebo.

    Nephropathy in Type 2 Diabetic  Patients 

    Hyperkalemia: In the Irbesartan Diabetic Nephropathy Trial (IDNT) (proteinuria ≥900  mg/day, and  serum  creatinine  ranging  from  1 to 3  mg/dL),  the  percent  of  patients  with  potassium >6 mEq/L  was  18.6%  in  the  Irbesartan Tablets  group  versus  6%  in  the  placebo  group.  Discontinuations due to hyperkalemia in the Irbesartan Tablets group were 2.1% versus 0.4% in the placebo  group.


    In IDNT, the adverse reactions were similar to those seen in patients with hypertension with  the exception of an increased incidence of orthostatic symptoms which occurred more frequently  in the  Irbesartan Tablets  versus  placebo  group:  dizziness  (10.2%  vs  6%),  orthostatic  dizziness  (5.4%  vs 2.7%) and orthostatic hypotension (5.4% vs  3.2%).

    6.2 Postmarketing Experience

    The  following  adverse  reactions  have  been  identified  during  postapproval  use  of  Irbesartan Tablets. Because  these  reactions  are  reported  voluntarily  from  a  population  of  uncertain  size,  it  is  not always  possible  to  estimate  reliably  their  frequency  or  to  establish  a  causal  relationship  to  drug exposure.


    Urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); anaphylactic reaction including anaphylactic shock; increased liver function tests; jaundice; hepatitis; hyperkalemia; thrombocytopenia; increased CPK; tinnitus.



  • 7 DRUG INTERACTIONS

    7.1 Agents Increasing Serum Potassium

    Coadministration of Irbesartan Tablets with other drugs that raise serum potassium levels may result  in hyperkalemia, sometimes severe. Monitor serum potassium in such  patients.

    7.2 Lithium

    Increases in serum lithium concentrations and lithium toxicity have been reported  with concomitant use of irbesartan and lithium. Monitor lithium levels in patients receiving  irbesartan  and  lithium.

    7.3 Non-Steroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

    In patients who are elderly, volume depleted (including those on diuretic therapy), or  with compromised renal function, coadministration of NSAIDs, including selective  COX-2 inhibitors, with angiotensin II receptor antagonists (including irbesartan) may result  in deterioration  of  renal  function,  including  possible  acute  renal  failure.  These  effects  are  usually reversible. Monitor renal function periodically in patients receiving irbesartan and  NSAID therapy.


    The  antihypertensive  effect  of  angiotensin  II  receptor  antagonists,  including  irbesartan,  may  be attenuated by NSAIDs including selective COX-2  inhibitors.

    7.4 Dual Blockade of the Renin-Angiotensin System (RAS)

    Dual  blockade  of  the  RAS  with  angiotensin  receptor  blockers,  ACE  inhibitors,  or  aliskiren  is associated  with  increased  risks  of  hypotension,  hyperkalemia,  and  changes  in  renal  function (including acute renal failure) compared to monotherapy. Most patients receiving  the combination of two RAS inhibitors do not obtain any additional benefit compared  to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood  pressure, renal function and electrolytes in patients on Irbesartan Tablets and other agents that affect the  RAS.


    Do  not  coadminister  aliskiren  with  Irbesartan Tablets  in  patients  with  diabetes.  Avoid  use  of  aliskiren with Irbesartan Tablets in patients with renal impairment (GFR <60  mL/min).

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Use  of  drugs  that  act  on  the  renin-angiotensin  system  during  the  second  and  third  trimesters  of pregnancy  reduces  fetal  renal  function  and  increases  fetal  and  neonatal  morbidity  and  death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and  skeletal  deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,  hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan Tablets as soon as  possible. These  adverse  outcomes  are  usually  associated  with  use  of  these  drugs  in  the  second  and  third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting  the renin-angiotensin system from other antihypertensive agents. Appropriate management  of maternal hypertension during pregnancy is important to optimize outcomes for both mother  and fetus.


    In  the  unusual  case  that  there  is  no  appropriate  alternative  to  therapy  with  drugs  affecting  the renin-angiotensin  system  for  a  particular  patient,  apprise  the  mother  of  the  potential  risk  to  the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment.  If oligohydramnios  is  observed,  discontinue  Irbesartan Tablets,  unless  it  is  considered  lifesaving  for  the mother.  Fetal  testing  may  be  appropriate,  based  on  the  week  of  pregnancy.  Patients    and physicians should be aware, however, that oligohydramnios may not appear until after the  fetus has  sustained  irreversible  injury.  Closely  observe  infants  with  histories  of  in  utero  exposure  to Irbesartan Tablets for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations  (8.4)].


    Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at  doses greater than the maximum recommended human dose (MRHD), fetuses showed  increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla.  Subcutaneous edema  also  occurred  in  fetuses  at  doses  about  4  times  the  MRHD  (based  on  body  surface  area). These  anomalies  occurred  when  pregnant  rats  received  irbesartan  through  Day  20  of  gestation but not when drug was stopped on gestation Day 15. The observed effects are believed to be  late gestational  effects  of  the  drug.  Pregnant  rabbits  given  oral  doses  of  irbesartan  equivalent  to  1.5 times the MRHD experienced a high rate of maternal mortality and abortion. Surviving  females had  a  slight  increase  in  early  resorptions  and  a  corresponding  decrease  in  live  fetuses  [see Nonclinical Toxicology  (13.2)].


    Radioactivity was present in the rat and rabbit fetus during late gestation and in rat  milk following oral doses of radiolabeled  irbesartan.

    8.3 Nursing Mothers

    It is not known whether irbesartan is excreted in human milk, but irbesartan or some  metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. Because  of the potential for adverse effects on the nursing infant, discontinue nursing or discontinue Irbesartan Tablets.

    8.4 Pediatric Use

    In infants with histories of in utero exposure to an angiotensin II receptor antagonist, observe  for hypotension,  oliguria,  and  hyperkalemia.  If  oliguria  occurs  support  blood  pressure  and  renal perfusion.  Exchange  transfusion  or  dialysis  may  be  required  as  means  of  reversing  hypotension and/or substituting for disordered renal  function.


    Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower  blood pressure effectively in pediatric patients ages 6 to 16  years.


    Irbesartan Tablets has not been studied in pediatric patients less than 6 years  old.

    8.5 Geriatric Use

    Of 4925 subjects receiving Irbesartan Tablets   in controlled clinical studies of hypertension,   911 (18.5%) were 65 years and over, while 150 (3%) were 75 years and over. No   overall differences  in  effectiveness or  safety were observed between  these subjects  and     younger subjects, but   greater  sensitivity  of  some  older  individuals  cannot  be  ruled  out  [see  Clinical  Pharmacology  (12.3)  and  Clinical  Studies  (14.1) ].

  • 10 OVERDOSAGE

    No  data  are  available  in  regard  to  overdosage  in  humans.  However,  daily  doses  of  900  mg  for 8  weeks  were  well-tolerated.  The  most  likely  manifestations  of  overdosage  are  expected  to  be hypotension  and  tachycardia;  bradycardia  might  also  occur  from  overdose.  Irbesartan  is  not removed by  hemodialysis.


    Acute  oral  toxicity  studies  with  irbesartan  in  mice  and  rats  indicated  acute  lethal  doses  were  in excess of 2000 mg/kg, about 25-fold and 50-fold the MRHD (300 mg) on a mg/m2  basis, respectively.

  • 11 DESCRIPTION

    Irbesartan Tablet is an angiotensin II receptor (AT 1  subtype) antagonist.

    Irbesartan is a non-peptide compound, chemically described as a  2-butyl-3-[p-(o-1H-tetrazol-5­ ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one.


    Its empirical formula is C25H28N6O, and the structural  formula:
    Structure


    Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water.
    Irbesartan Tablets USP is available for oral administration in unscored tablets containing 75 mg, 150 mg and 300 mg of Irbesartan.
    Inactive ingredients include: lactose, povidone k-30, croscarmellose sodium and magnesium stearate.


  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis.

    Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2  receptor and no agonist activity.

    Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure.

    Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion  channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis.

    12.2 Pharmacodynamics

    In healthy subjects, single oral irbesartan doses of up to 300 mg produced  dose-dependent inhibition  of  the  pressor  effect  of  angiotensin  II  infusions.  Inhibition  was  complete  (100%)  4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24  hours (60% and 40% at 300 mg and 150 mg,  respectively).


    In hypertensive patients, angiotensin II receptor inhibition following chronic administration  of irbesartan  causes  a  1.5-fold  to  2-fold  rise  in  angiotensin  II  plasma  concentration  and  a  2-fold  to  3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline  following irbesartan administration, but serum potassium levels are not significantly affected  at recommended  doses.

    In  hypertensive  patients,  chronic  oral  doses  of  irbesartan  (up  to  300  mg)  had  no  effect  on glomerular  filtration  rate,  renal  plasma  flow,  or  filtration  fraction.  In  multiple  dose  studies  in hypertensive  patients,  there  were  no  clinically  important  effects  on  fasting  triglycerides,  total cholesterol,  HDL-cholesterol,  or  fasting  glucose  concentrations.  There  was  no  effect  on  serum uric acid during chronic oral administration, and no uricosuric  effect.

    12.3 Pharmacokinetics

    Absorption

    The  oral  absorption  of  irbesartan  is  rapid  and  complete  with  an  average  absolute  bioavailability of  60%  to  80%.  Following  oral  administration  of  Irbesartan Tablets,  peak  plasma  concentrations  of irbesartan  are  attained  at  1.5  to  2  hours  after  dosing.  Food  does  not  affect  the  bioavailability  of irbesartan.


    Irbesartan exhibits linear pharmacokinetics over the therapeutic dose  range.  

     

    Distribution

    Irbesartan is 90% bound to serum proteins (primarily albumin and α1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53 to 93 liters.

    Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of lactating rats.


    Elimination

    Total plasma and renal clearances are in the range of 157 to 176 mL/min and 3 to 3.5 mL/min, respectively. The terminal elimination half-life of irbesartan averages 11 to 15 hours. Steady- state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing and is not clinically relevant.


    Metabolism

    Irbesartan is an orally active agent that does not require biotransformation into an active form. Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan’s pharmacologic activity.

    In vitro studies indicate irbesartan is oxidized primarily by CYP2C9; metabolism by CYP3A4 is negligible.


    Excretion

    Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.

     

    Specific  Populations

     

    Sex

    No sex-related differences in pharmacokinetics are observed in healthy elderly (age 65 to 80 years) or in healthy young (age 18 to 40 years) subjects. In studies of hypertensive patients, there is no sex difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan are observed in females (11% to 44%). No sex-related dosage adjustment is necessary.

     

    Geriatrics

    In elderly subjects (age 65 to 80 years), irbesartan elimination half-life is not significantly altered, but AUC and Cmax values are about 20% to 50% greater than those of young subjects (age 18 to 40 years). No dosage adjustment is necessary in the elderly. 


    Race / Ethnicity

    In healthy black subjects, irbesartan AUC values are approximately 25% greater than whites; there is no difference in Cmax values. 


    Renal  Impairment

    The pharmacokinetics of irbesartan is not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by hemodialysis. No dosage   adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted [see Warnings and Precautions (5.2) and Dosage and Administration (2.4)]. 


    Hepatic  Insufficiency

    The pharmacokinetics of irbesartan following repeated oral administration are not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.


    Drug- Drug  Interactions

    In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with  the  known  cytochrome  CYP2C9  substrates/inhibitors  sulphenazole,  tolbutamide    and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin were negligible. Based on in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.
    In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days has no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan are not affected by coadministration of nifedipine or hydrochlorothiazide.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No evidence of carcinogenicity was observed when irbesartan was administered at dosages of  up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for  up to  2  years.  For  male  and  female  rats,  500  mg/kg/day  provided  an  average  systemic  exposure  to irbesartan  (AUC0-24 hours,  bound  plus  unbound)  about  3  and  11  times,  respectively,  the  average systemic  exposure  in  humans  receiving  the  maximum  recommended  dose  (MRD)  of  300  mg irbesartan/day,  whereas  1000  mg/kg/day  (administered  to  females  only)  provided  an  average systemic  exposure  about  21  times  that  reported  for  humans  at  the  MRD.  For  male  and  female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively,  the human exposure at 300  mg/day.


    Irbesartan  was  not  mutagenic  in  a  battery  of  in  vitro  tests  (Ames  microbial  test,  rat  hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative  in several tests for  induction  of  chromosomal  aberrations  (in  vitro—human  lymphocyte assay; in vivo—mouse micronucleus  study).


    Irbesartan  had  no  adverse  effects  on  fertility  or  mating  of  male  or  female  rats  at  oral  dosages ≤650  mg/kg/day,  the  highest  dose  providing  a  systemic  exposure  to  irbesartan  (AUC0-24 hours, bound plus unbound) about 5 times that found in humans receiving the MRD of 300  mg/day.

    13.2 Animal Toxicology and/or Pharmacology

    When pregnant rats were treated with irbesartan from Day 0 to Day 20 of gestation (oral doses  of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal  pelvic cavitation,  hydroureter  and/or  absence  of  renal  papilla  were  observed  in  fetuses  at  dosages ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD],  300 mg/day,  on  a  body  surface  area  basis).  Subcutaneous  edema  was  observed  in  fetuses  at  dosages ≥180  mg/kg/day  (about  4  times  the  MRHD  on  a  body  surface  area  basis).  As  these  anomalies  were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and  450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects  of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated  with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times  the MRHD  on  a  body  surface  area  basis)  had  a  slight  increase  in  early  resorptions  and  a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in  rats and  rabbits.

  • 14 CLINICAL STUDIES

    14.1 Hypertension

    The antihypertensive effects of Irbesartan Tablets were examined in 7 placebo-controlled 8- to 12-week trials in patients with baseline diastolic blood pressures of 95 to 110 mmHg. Doses of 1 to 900 mg were included in these trials in order to fully explore the dose-range of irbesartan. These studies allowed comparison of once- or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by sex, age, and race. Two of the seven placebo-controlled trials identified above examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination.

    The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1 to 900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 mg and 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hours post dose) effects after 6 to 12 weeks of treatment compared to placebo, of about 8 to 10/5 to 6 mmHg and 8 to 12/5 to 8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300 mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2.
    Figure 1 and 2

    Once-daily  administration  of  therapeutic  doses  of  irbesartan  gave  peak  effects  at  around  3  to  6 hours and, in one ambulatory blood pressure monitoring study, again around 14 hours. This  was seen with both once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and  diastolic response were generally between 60% and  70%. In a continuous ambulatory blood  pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour  responses similar to those observed in patients receiving twice-daily dosing at the same total daily  dose.


    In controlled trials, the addition of irbesartan to hydrochlorothiazide doses of 6.25 mg, 12.5  mg, or  25  mg  produced  further  dose-related  reductions  in  blood  pressure  similar  to  those  achieved with the same monotherapy dose of irbesartan. HCTZ also had an approximately additive  effect.


    Analysis  of  age,  sex,  and  race  subgroups  of  patients  showed  that  men  and  women,  and  patients over  and  under  65  years  of  age,  had  generally  similar  responses.  Irbesartan  was  effective  in reducing  blood  pressure  regardless  of  race,  although  the  effect  was  somewhat  less  in  blacks (usually a low-renin  population).


    The effect of irbesartan is apparent after the first dose, and it is close to its full observed effect  at 2  weeks.  At  the  end  of  an  8-week  exposure,  about  2/3  of  the  antihypertensive  effect  was  still present one week after the last dose. Rebound hypertension was not observed. There  was essentially no change in average heart rate in irbesartan-treated patients in controlled  trials.


    14.2 Nephropathy in Type 2 Diabetic Patients

    The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized, placebo- and active- controlled, double-blind, multicenter study conducted worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP >135 mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine  1  to  3  mg/dL  in  females  or  1.2  to  3  mg/dL  in  males  and  proteinuria ≥900 mg/day). Patients were randomized to receive Irbesartan Tablets 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were titrated to a maintenance dose of Irbesartan 300 mg, or amlodipine 10 mg, as tolerated. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers) were added as needed to achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood pressure if higher than 160 mmHg) for patients in all groups.

    The study population was 66.5% male, 72.9% below 65 years of age, and 72% White (Asian/Pacific Islander 5%, Black 13.3%, Hispanic 4.8%). The mean baseline seated systolic and diastolic blood pressures were 159 mmHg and 87 mmHg, respectively. The patients entered the trial with a mean serum creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day.

    The mean blood pressure achieved was 142/77 mmHg for Irbesartan, 142/76 mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83% of patients received the target dose of irbesartan more than 50% of the time. Patients were followed for a mean duration of 2.6 years.

    The primary composite endpoint was the time to occurrence of any one of the following events: doubling of baseline serum creatinine, end-stage renal disease (ESRD; defined by serum creatinine ≥6 mg/dL, dialysis, or renal transplantation), or death. Treatment with Irbesartan Tablets resulted in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1). Treatment with Irbesartan Tablets also reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%), but had no significant effect on ESRD alone and no effect on overall mortality (see Table 1).
    Figure 3:IDNT: Kaplan-Meier Estimates of Primary Endpoint
    (Doubling of Serum Creatinine, End-Stage Renal Disease or All- Cause Mortality)
    Figure 3
    The percentages of patients experiencing an event during the course of the study can be seen in Table 1 below:
    Table 1:IDNT: Components of Primary Composite Endpoint

     Irbesartan
    N=579
    (%)     		Comparison With  Placebo  Comparison With  Amlodipine
       Placebo
    N=569 (%)    		 Hazard
     Ratio    		 95%
      CI    		Amlodipine
    N=567 (%)    		 Hazard
    Ratio    		95%
      CI     
    Primary Composite Endpoint  32.639     0.8 0.66 to 0.97
    (p=0.0234)     		 41.10.77  0.63 to 0.93
     Breakdown of first occurring event contributing to primary endpoint
     2x creatinine 14.219.5 ---      ---22.8 --- --- 
     ESRD 7.48.3 --- --- 8.8 --- --- 
     Death 11.111.2 --- --- 9.5  --- ---
     Incidence of total events over entire period of follow-up
      2x creatinine 16.9 23.7 0.670.52 to 0.87 25.4 0.63 0.49 to 0.81 
     ESRD 14.217.8  0.770.57 to 1.03 18.30.77 0.57 to 1.03 
      Death 15 16.30.92 0.69 to 1.23 14.6 1.04 0.77 to 1.4 

    The secondary endpoint of the study was a composite of cardiovascular mortality and morbidity (myocardial infarction, hospitalization for heart failure, stroke with permanent neurological deficit, amputation). There were no statistically significant differences among treatment  groups in these endpoints. Compared with placebo, Irbesartan significantly reduced proteinuria by about 27%, an effect that was evident within 3 months of starting therapy. Irbesartan significantly reduced the rate of loss of renal function (glomerular filtration rate), as measured by the reciprocal of the serum creatinine concentration, by 18.2%.
    Table 2 presents results for demographic subgroups. Subgroup analyses are difficult to interpret, and it is not known whether these observations represent true differences or chance effects. For the primary endpoint, Irbesartan’s favorable effects were seen in patients also taking other antihypertensive medications (angiotensin II receptor antagonists, angiotensin-converting­ enzyme inhibitors, and calcium channel blockers were not allowed), oral hypoglycemic agents, and lipid-lowering agents.


    Table 2: IDNT: Primary Efficacy Outcome Within Subgroups

    Baseline
    Factors
         		Irbesartan
    N=579
    (%)
     
         		Comparison With Placebo
     Placebo
    N=569
    (%)    		Hazard
     Ratio     		95%
     Cl     
     Sex
     Male 27.536.7  0.680.53 to 0.88 
     Female 42.344.6 0.98 0.72 to 1.34 
     Race
     White 29.537.3 0.75 0.6 to 0.95 
     Non-White 42.643.5 0.95 0.67 to 1.34 
     Age (years)
     <65 31.839.9 0.77 0.62 to 0.97 
     ≥6535.1 36.8 0.88 0.61 to 1.29 

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Irbesartan Tablets USP 75 mg are available as white to off white, oval shaped, biconvex, uncoated tablet, debossed with “L131” on one side and “75” on other side. They are supplied as follows:

    NDC: 62332-041-30                Bottles of 30

    NDC: 62332-041-90                Bottles of 90

    NDC: 62332-041-31                Bottles of 100

    NDC: 62332-041-71                Bottles of 500

    NDC: 62332-041-91                Bottles of 1000


    Irbesartan Tablets USP 150 mg are available as white to off white, oval shaped, biconvex, uncoated tablet, debossed with “L132” on one side and “150” on other side. They are supplied as follows:

    NDC: 62332-042-30                Bottles of 30

    NDC: 62332-042-90                Bottles of 90

    NDC: 62332-042-31                Bottles of 100

    NDC: 62332-042-71                Bottles of 500

    NDC: 62332-042-91                Bottles of 1000


    Irbesartan Tablets USP 300 mg are available as white to off white, oval shaped, biconvex, uncoated tablet, debossed with “L133” on one side and “300” on other side. They are supplied as follows:

    NDC: 62332-043-30                Bottles of 30

    NDC: 62332-043-90                Bottles of 90

    NDC: 62332-043-31                Bottles of 100

    NDC: 62332-043-71                Bottles of 500

    NDC: 62332-043-91                Bottles of 1000


    Store  at  25°C  (77°F);  excursions  permitted  to  15°C - 30°C  (59°F - 86°F)  [see  USP  Controlled Room  Temperature].

  • 17 PATIENT COUNSELING INFORMATION

    Pregnancy

    Advise  female  patients  of  childbearing  age  about  the  consequences  of  exposure  to  Irbesartan Tablets during pregnancy. Discuss treatment options with women planning to become pregnant.  Patients should be asked to report pregnancies to their physicians as soon as  possible.


    Potassium  Supplements

    Advise patients receiving Irbesartan Tablets not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider [see Drug Interactions  (7.1)].

     

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    For more information, you can also call Alembic Pharmaceuticals Limited at 1-866-210-9797.


    Manufactured by:

    Alembic Pharmaceuticals Limited

    (Formulation Division),

    Panelav 389350, Gujarat, India


    Manufactured for:

    Alembic Pharmaceuticals, Inc.

    750 Route 202, Bridgewater, NJ 08807

    USA

    Revised: 08/2018

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 75 mg

    NDC: 62332-041-30
    Irbesartan
    Tablets, USP
    75 mg
    Rx only
    30 Tablets
    Alembic
    30 Tablets

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 150 mg

    NDC: 62332-042-30
    Irbesartan
    Tablets, USP
    150 mg
    Rx only
    30 Tablets
    Alembic
    30 Tablets

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 300 mg

    NDC: 62332-043-30
    Irbesartan
    Tablets, USP
    300 mg
    Rx only
    30 Tablets
    Alembic
    30 Tablets

  • INGREDIENTS AND APPEARANCE
    IRBESARTAN 
    irbesartan tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 62332-041
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    IRBESARTAN (UNII: J0E2756Z7N) (IRBESARTAN - UNII:J0E2756Z7N) IRBESARTAN75 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    POVIDONE K30 (UNII: U725QWY32X)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITE (White to Off White) Scoreno score
    ShapeOVALSize11mm
    FlavorImprint Code L131;75
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 62332-041-3030 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    2NDC: 62332-041-9090 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    3NDC: 62332-041-31100 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    4NDC: 62332-041-71500 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    5NDC: 62332-041-911000 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09123607/01/2016
    IRBESARTAN 
    irbesartan tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 62332-042
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    IRBESARTAN (UNII: J0E2756Z7N) (IRBESARTAN - UNII:J0E2756Z7N) IRBESARTAN150 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    POVIDONE K30 (UNII: U725QWY32X)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITE (White to Off White) Scoreno score
    ShapeOVALSize14mm
    FlavorImprint Code L132;150
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 62332-042-3030 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    2NDC: 62332-042-9090 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    3NDC: 62332-042-31100 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    4NDC: 62332-042-71500 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    5NDC: 62332-042-911000 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09123607/01/2016
    IRBESARTAN 
    irbesartan tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 62332-043
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    IRBESARTAN (UNII: J0E2756Z7N) (IRBESARTAN - UNII:J0E2756Z7N) IRBESARTAN300 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    POVIDONE K30 (UNII: U725QWY32X)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITE (White to Off White) Scoreno score
    ShapeOVALSize17mm
    FlavorImprint Code L133;300
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 62332-043-3030 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    2NDC: 62332-043-9090 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    3NDC: 62332-043-31100 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    4NDC: 62332-043-71500 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    5NDC: 62332-043-911000 in 1 BOTTLE; Type 0: Not a Combination Product07/01/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09123607/01/2016
    Labeler - Alembic Pharmaceuticals Inc. (079288842)
    Establishment
    NameAddressID/FEIBusiness Operations
    Alembic Pharmaceuticals Limited650574671MANUFACTURE(62332-041, 62332-042, 62332-043)
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