Secondary hyperparathyroidism

Adults

Treatment of secondary hyperparathyroidism (HPT) in adult patients with end-stage renal disease (ESRD) on maintenance dialysis therapy.

Paediatric population

Treatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end-stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy.

Cinacalcet Tablets may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate.

Parathyroid carcinoma and primary hyperparathyroidism in adults

Reduction of hypercalcemia in adult patients with:

• parathyroid carcinoma.
• primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.

Posology

Secondary hyperparathyroidism: Adults and elderly (> 65 years)

The recommended starting dose for adults is 30 mg once per day. Cinacalcet Tablets should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in dialysis patients of between 150-300 pg/mL (15.9-31.8 pmol/L) in the intact PTH (iPTH) assay. PTH levels should be assessed at least 12 hours after dosing with Cinacalcet Tablets. Reference should be made to current treatment guidelines.

PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Cinacalcet Tablets. PTH should be monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-intact PTH (biPTH) may be used to measure PTH levels; treatment with Cinacalcet Tablets does not alter the relationship between iPTH and biPTH.

Dose adjustment based on serum calcium levels

Corrected serum calcium should be measured and monitored and should be at or above the lower limit of the normal range prior to administration of first dose of Cinacalcet Tablets. The normal calcium range may differ depending on the methods used by your local laboratory.

During dose titration, serum calcium levels should be monitored frequently, and within 1 week of initiation or dose adjustment of Cinacalcet Tablets. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. In the event that corrected serum calcium levels fall below 8.4 mg/dL (2.1 mmol/L) and/or symptoms of hypocalcaemia occur the following management is recommended:

Pediatric population

Corrected serum calcium should be in the upper range of, or above, the age-specified reference interval prior to administration of first dose of Cinacalcet Tablets, and closely monitored. The normal calcium range differs depending on the methods used by your local laboratory and the age of the child/patient.

The recommended starting dose for children aged ≥ 3 years to < 18 years is ≤ 0.20 mg/kg once daily based on the patient's dry weight (see table 1).

The dose can be increased to achieve a desired target iPTH range. The dose should be increased sequentially through available dose levels (see table 1) no more frequently than every 4 weeks. The dose can be increased up to a maximum dose of 2.5 mg/kg/day, not to exceed a total daily dose of 180 mg.

Dose adjustment based on PTH levels

PTH levels should be assessed at least 12 hours after dosing with Cinacalcet Tablets and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Cinacalcet Tablets.

The dose should be adjusted based on iPTH as shown below:

• If iPTH is < 150 pg/mL (15.9 pmol/L) and ≥ 100 pg/mL (10.6 pmol/L), decrease the dose of Cinacalcet Tablets to the next lower dose.
• If iPTH < 100 pg/mL (10.6 pmol/L), stop Cinacalcet Tablets treatment, restart Cinacalcet Tablets at the next lower dose once the iPTH is > 150 pg/mL (15.9 pmol/L). If Cinacalcet Tablets treatment has been stopped for more than 14 days, restart at the recommended starting dose.

Dose adjustment based on serum calcium levels

Serum calcium should be measured within 1 week after initiation or dose adjustment of Cinacalcet Tablets.

Once the maintenance dose has been established, weekly measurement of serum calcium is recommended. Serum calcium levels in paediatric patients should be maintained within the normal range. If serum calcium levels decrease below the normal range or symptoms of hypocalcaemia occur, appropriate dose adjustment steps should be taken as shown in table 2 below:

If the dose has been stopped, corrected serum calcium should be measured within 5 to 7 days

The safety and efficacy of Cinacalcet Tablets in children aged less than 3 years for the treatment of secondary hyperparathyroidism have not been established.

Switch from etelcalcetide to Cinacalcet Tablets

The switch from etelcalcetide to Cinacalcet Tablets and the appropriate wash out period has not been studied in patients. In patients who have discontinued etelcalcetide, Cinacalcet Tablets should not be initiated until at least three subsequent haemodialysis sessions have been completed, at which time serum calcium should be measured. Ensure serum calcium levels are within the normal range before Cinacalcet Tablets is initiated.

Parathyroid carcinoma and primary hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose of Cinacalcet Tablets for adults is 30 mg twice per day. The dose of Cinacalcet Tablets should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium concentration to or below the upper limit of normal.

Serum calcium should be measured within 1 week after initiation or dose adjustment of Cinacalcet Tablets. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months. After titration to the maximum dose of Cinacalcet Tablets, serum calcium should be periodically monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of Cinacalcet Tablets therapy should be considered.

Paediatric population

The safety and efficacy of Cinacalcet Tablets in children for the treatment of parathyroid carcinoma and primary hyperparathyroidism have not been established. No data are available.

Hepatic impairment

No change in starting dose is necessary. Cinacalcet Tablets should be used with caution in patients with moderate to severe hepatic impairment and treatment should be closely monitored during dose titration and continued treatment.

Method of administration

For oral use.

Tablets should be taken whole and should not be chewed, crushed or divided.

It is recommended that Cinacalcet Tablets be taken with food or shortly after a meal, as studies have shown that bioavailability of cinacalcet is increased when taken with food.

Cinacalcet Tablets is also available as granules for paediatric use. Children who require doses lower than 30 mg, or who are unable to swallow tablets should receive Cinacalcet Tablets granules.

Serum calcium

Life threatening events and fatal outcomes associated with hypocalcaemia may be reported in adult and paediatric patients treated with Cinacalcet Tablets. Manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and convulsions. Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia secondary to hypocalcaemia. Cases of QT prolongation and ventricular arrhythmia may be reported in patients treated with cinacalcet. Caution is advised in patients with other risk factors for QT prolongation such as patients with known congenital long QT syndrome or patients receiving medicinal products known to cause QT prolongation.

Since cinacalcet lowers serum calcium, patients should be monitored carefully for the occurrence of hypocalcaemia. Serum calcium should be measured within 1 week after initiation or dose adjustment of Cinacalcet Tablets.

Adults

Cinacalcet Tablets treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range.

In CKD patients receiving dialysis who were administered Cinacalcet Tablets may lead to lower the serum calcium value less than 7.5 mg/dL (1.9 mmol/L).

Paediatric population

Cinacalcet Tablets should only be initiated for the treatment of secondary HPT in children ≥ 3 years old with ESRD on maintenance dialysis therapy, in whom secondary HPT is not adequately controlled with standard of care therapy, where serum calcium is in the upper range of, or above, the age-specified reference interval. Closely monitor serum calcium levels and patient compliance during treatment with cinacalcet. Do not initiate cinacalcet or increase the dose if non-compliance is suspected.

Prior to initiating cinacalcet and during treatment, consider the risks and benefits of treatment and the ability of the patient to comply with the recommendations to monitor and manage the risk of hypocalcaemia.

Inform paediatric patients and/or their caregivers about the symptoms of hypocalcaemia and about the importance of adherence to instructions about serum calcium monitoring, and posology and method of administration.

CKD patients not on dialysis

Cinacalcet is not indicated for CKD patients not on dialysis. The adult CKD patients not on dialysis treated with cinacalcet may have an increased risk for hypocalcaemia (serum calcium levels < 8.4 mg/dL [2.1 mmol/L]) compared with cinacalcet-treated CKD patients on dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

Seizures

Cases of seizures may be reported in patients treated with Cinacalcet Tablets. The threshold for seizures may be lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Cinacalcet Tablets, particularly in patients with a history of a seizure disorder.

Hypotension and/or worsening heart failure

Cases of hypotension and/or worsening heart failure may be reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet could not be completely excluded and may be mediated by reductions in serum calcium levels.

Co-administration with other medicinal products

Administer Cinacalcet Tablets with caution in patients receiving any other medicinal products known to lower serum calcium. Closely monitor serum calcium.

Patients receiving Cinacalcet Tablets should not be given etelcalcetide. Concurrent administration may result in severe hypocalcaemia.

General

Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 1.5 times the upper limit of normal with the iPTH assay. If PTH levels decrease below the recommended target range in patients treated with Cinacalcet Tablets, the dose of Cinacalcet Tablets and/or vitamin D sterols should be reduced or therapy discontinued.

Testosterone levels

Testosterone levels are often below the normal range in patients with end-stage renal disease. The clinical significance of these reductions in serum testosterone is unknown.

Hepatic impairment

Due to the potential for 2-to-4-fold higher plasma levels of cinacalcet in patients with moderate to severe hepatic impairment (Child-Pugh classification), Cinacalcet Tablets should be used with caution in these patients and treatment should be closely monitored.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Positive Urine Glucose Test

Medicinal products known to reduce serum calcium

Concurrent administration of other medicinal products known to reduce serum calcium and Cinacalcet Tablets may result in an increased risk of hypocalcaemia. Patients receiving Cinacalcet Tablets should not be given etelcalcetide.

Effect of other medicinal products on cinacalcet

Dose adjustment of Cinacalcet Tablets may be required if a patient receiving Cinacalcet Tablets initiates or discontinues therapy with a strong inhibitor (e.g., ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (e.g., rifampicin) of this enzyme.

Dose adjustment may be necessary if a patient starts or stops smoking or when concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.

Calcium carbonate

Co-administration of calcium carbonate (single 1,500 mg dose) will not alter the pharmacokinetics of cinacalcet.

Sevelamer

Co-administration of sevelamer (2,400 mg tid) may not affect the pharmacokinetics of cinacalcet.

Pantoprazole

Co-administration of pantoprazole (80 mg od) may not alter the pharmacokinetics of cinacalcet.

Effect of cinacalcet on other medicinal products

Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6):

Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments of concomitant medicinal products may be required when Cinacalcet Tablets is administered with individually titrated, narrow therapeutic index substances that are predominantly metabolised by CYP2D6 (e.g., flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine).

Desipramine: Concurrent administration of 90 mg cinacalcet once daily with 50 mg desipramine, a tricyclic antidepressant metabolised primarily by CYP2D6, may increase desipramine exposure in CYP2D6 extensive metabolisers.

Dextromethorphan: Multiple doses of 50 mg cinacalcet may increase the AUC of 30 mg dextromethorphan (metabolised primarily by CYP2D6) by 11-fold in CYP2D6 extensive metabolisers.

Warfarin: Multiple oral doses of cinacalcet may not affect the pharmacokinetics or pharmacodynamics (as measured by prothrombin time and clotting factor VII) of warfarin. Cinacalcet is not an inducer of CYP3A4, CYP1A2 or CYP2C9 in humans.

Midazolam: Co-administration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a CYP3A4 and CYP3A5 substrate, may not alter the pharmacokinetics of midazolam. Cinacalcet would not affect the pharmacokinetics of those classes of medicines that are metabolised by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine and tacrolimus.

Pregnancy

Cinacalcet Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is not known whether cinacalcet is excreted in human milk. Following careful benefit/risk assessment, a decision should be made to discontinue either breast-feeding or treatment with Cinacalcet Tablets.

Fertility

There are no clinical data relating to the effect of cinacalcet on fertility.

Cinacalcet Tablets may have major influence on the ability to drive and use machines, since dizziness and seizures may be reported by patients taking this medicinal product.

Summary of the safety profile

Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism

Based on available data from patients receiving cinacalcet in placebo-controlled studies and single arm studies the most commonly reported adverse reactions were nausea and vomiting. Nausea and vomiting were mild to moderate in severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of undesirable effects was mainly due to nausea and vomiting.

Tabulated list of adverse reactions

Adverse reactions, considered at least possibly attributable to cinacalcet treatment in the placebo-controlled studies and single-arm studies based on best-evidence assessment of causality are listed below using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are:

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions including angioedema and urticaria have been identified during post-marketing use of cinacalcet. The frequencies of the individual preferred terms including angioedema and urticaria cannot be estimated from available data.

Hypotension and/or worsening heart failure

There have been reports of idiosyncratic cases of hypotension and/or worsening heart failure in cinacalcet treated patients with impaired cardiac function in post-marketing safety surveillance, the frequencies of which cannot be estimated from available data.

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia have been identified during post-marketing use of cinacalcet, the frequencies of which cannot be estimated from available data (see section 4.4).

Paediatric population

The safety of Cinacalcet for the treatment of secondary HPT in paediatric patients with ESRD receiving dialysis was evaluated in two randomised controlled studies and one single-arm study (see section 5.1). Among all paediatric subjects exposed to cinacalcet in clinical studies a total of 19 subjects (24.1%; 64.5 per 100 subject years) had at least one adverse event of hypocalcaemia. A fatal outcome was reported in a paediatric clinical trial patient with severe hypocalcaemia (see section 4.4).

Cinacalcet should be used in paediatric patients only if the potential benefit justifies the potential risk

To report any side effect(s):

·      Saudi Arabia:

National Pharmacovigilance Center (NPC)

SFDA Call center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/ 

·      Other GCC States

Please contact the relevant competent authority.

Doses titrated up to 300 mg once daily have been administered to adult patients receiving dialysis without adverse outcome. A daily dose of 3.9 mg/kg may be prescribed to a paediatric patient receiving dialysis with subsequent mild stomach ache, nausea and vomiting.

Overdose of Cinacalcet Tablets may lead to hypocalcaemia. In the event of overdose, patients should be monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and supportive. Since cinacalcet is highly protein bound, haemodialysis is not an effective treatment for overdose.

Pharmacotherapeutic group: Calcium homeostasis, anti-parathyroid agents. ATC code: H05BX01.

Mechanism of action

The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet is a calcimimetic agent which directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

Reductions in PTH levels correlate with cinacalcet concentration.

After steady state is reached, serum calcium concentrations remain constant over the dosing interval

Absorption: After oral administration of cinacalcet, maximum plasma cinacalcet

concentration is achieved in approximately 2 to 6 hours. Based on between-study

comparisons, the absolute bioavailability of cinacalcet in fasted subjects has been estimated to be about 20-25%. Administration of cinacalcet with food results in an approximate 50-80% increase in cinacalcet bioavailability. Increases in plasma cinacalcet concentration are similar, regardless of the fat content of the meal.

At doses above 200 mg, the absorption was saturated probably due to poor solubility.

Distribution: The volume of distribution is high (approximately 1,000 litres), indicating extensive distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood cells.

After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state levels of cinacalcet are achieved within 7 days with minimal accumulation. The pharmacokinetics of cinacalcet does not change over time.

Biotransformation: Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the contribution of CYP1A2 has not been characterised clinically). The major circulating metabolites are inactive. Based on in vitro data, cinacalcet is a strong inhibitor of CYP2D6, but is neither an inhibitor of other CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 nor an inducer of CYP1A2, CYP2C19 and CYP3A4.

Elimination: After administration of a 75 mg radiolabelled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolised by oxidation followed by conjugation. Renal excretion of metabolites was the prevalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the faeces.

Linearity/non-linearity: The AUC and Cmax of cinacalcet increase approximately linearly over the dose range of 30 to 180 mg once daily.

Pharmacokinetic/pharmacodynamic relationship(s): Soon after dosing, PTH begins to decrease until a nadir at approximately 2 to 6 hours post dose, corresponding with cinacalcet C_max. Thereafter, as cinacalcet levels begin to decline, PTH levels increase until 12 hours post-dose, and then PTH suppression remains approximately constant to the end of the once daily dosing interval. PTH levels in cinacalcet clinical trials were measured at the end of the dosing interval.

Elderly: There are no clinically relevant differences due to age in the pharmacokinetics of cinacalcet.

Renal insufficiency: The pharmacokinetic profile of cinacalcet in patients with mild,

moderate, and severe renal insufficiency, and those on haemodialysis or peritoneal dialysis is comparable to that in healthy volunteers.

Hepatic insufficiency: Mild hepatic impairment did not notably affect the pharmacokinetics of cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in subjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.

Protein binding of cinacalcet is not affected by impaired hepatic function. Because doses are titrated for each subject based on safety and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic impairment.

Gender: Clearance of cinacalcet may be lower in women than in men. Because doses are titrated for each subject, no additional dose adjustment is necessary based on gender.

Pediatric population: The pharmacokinetics of cinacalcet was studied in pediatric patients with ESRD receiving dialysis aged 3 to 17 years of age. After single and multiple once daily oral doses of cinacalcet, plasma cinacalcet concentrations (Cmax and AUC values after normalization by dose and weight) were similar to those observed in adult patients.

A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no significant impact of age, sex, race, body surface area, and body weight on cinacalcet pharmacokinetics.

Smoking: Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of CYP1A2-mediated metabolism. If a patient stops or starts smoking, cinacalcet plasma levels may change and dose adjustment may be necessary.

Cinacalcet was not teratogenic in rabbits when given at a dose of 0.4 times, on an AUC basis, the maximum human dose for secondary HPT (180 mg daily). The non-teratogenic dose in rats was 4.4 times, on an AUC basis, the maximum dose for secondary HPT. There were no effects on fertility in males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small population of patients administered a maximum clinical dose of 360 mg daily would be approximately half those given above).

In pregnant rats, there were slight decreases in body weight and food consumption at the highest dose. Decreased foetal weights were seen in rats at doses where dams had severe hypocalcaemia. Cinacalcet has been shown to cross the placental barrier in rabbits.

Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicology studies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts and lens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but were not observed in dogs or monkeys or in clinical studies where cataract formation was monitored. Cataracts are known to occur in rodents as a result of hypocalcaemia.

In in vitro studies, IC50 values for the serotonin transporter and KATP channels were found to be 7 and 12-fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the same experimental conditions. The clinical relevance is unknown, however, the potential for cinacalcet to act on these secon

In toxicity studies in juvenile dogs, tremors secondary to decreased serum calcium, emesis, decreased body weight and body weight gain, decreased red cell mass, slight decreases in bone densitometry parameters, reversible widening of the growth plates of long bones, and histological lymphoid changes (restricted to the thoracic cavity and attributed to chronic emesis) were observed. All of these effects were seen at a systemic exposure, on an AUC basis, approximately equivalent to the exposure in patients at the maximum dose for secondary HPT.

Lanacet 30 (Cinacalcet Hydrochloride Tablets 30 mg)

Lactose Monohydrate

Microcrystalline Cellulose

Crospovidone

Colloidal silicon dioxide

Purified Water

Magnesium stearate

Instacoat universal green

Coating (Instacoat Universal green A05G31707): Hypromellose, Lactose monohydrate, Triacetin, Titanium dioxide, Yellow Iron Oxide, FD, and C Blue No. 2 Al. Lake

Lanacet 60 (Cinacalcet Hydrochloride Tablets 60 mg)

Lactose Monohydrate

Microcrystalline Cellulose

Crospovidone

Colloidal silicon dioxide

Purified Water

Magnesium stearate

Instacoat universal green

Coating (Instacoat Universal green A05G31707): Hypromellose, Lactose monohydrate, Triacetin, Titanium dioxide, Yellow Iron Oxide, FD, and C Blue No. 2 Al. Lake

Lanacet 90 (Cinacalcet Hydrochloride Tablets 90 mg)

Lactose Monohydrate

Microcrystalline Cellulose

Crospovidone

Colloidal silicon dioxide

Purified Water

Magnesium stearate

Instacoat universal green

Coating (Instacoat Universal green A05G31707): Hypromellose, Lactose monohydrate, Triacetin, Titanium dioxide, Yellow Iron Oxide, FD, and C Blue No. 2 Al. Lake

None known.

Do not store above 30°C.

Cinacalcet tablets are packed in Clear PVC/PE/PVdC - Aluminum foil blister pack

Blister Pack

Cinacalcet tablets will be packed in,

30 mg & 60 mg tablets: 10 tablets in Clear PVC/PE/PVdC – Aluminum foil blister and such 1 blister packed in a carton along with pack insert.

90 mg tablets: 14 tablets in Clear PVC/PE/PVdC – Aluminum foil blister and such 1 blister packed in a carton along with pack insert.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.