Mit's Linctus Codeine

Cough And Upper Respiratory Allergy Symptoms

Mit's Linctus Codeine is indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older.

Important Limitations Of Use

Not indicated for pediatric patients under 18 years of age.

Adults 18 Years Of Age And Older

Mit's Linctus Codeine should be orally administered in a dose of 10 mL every 12 hours, not to exceed 2 doses (20 mL) in 24 hours.

Administration Information

Administer Mit's Linctus Codeine by the oral route only, with or without food. Shake well before use. Measure with an accurate milliliter measuring device. Do not use a household teaspoon to measure the dose.

Mit's Linctus Codeine is contraindicated for:

• All children younger than 12 years of age.
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
• Patients with known hypersensitivity to codeine, chlorpheniramine or any of the inactive ingredients of Mit's Linctus Codeine. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Ultra-Rapid Metabolism Of Codeine And Other Risk Factors For Life-threatening Respiratory Depression In Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Mit's Linctus Codeine is contraindicated in all children younger than 12 years of age.
• Mit's Linctus Codeine is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
• Avoid the use of Mit's Linctus Codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• When prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

Nursing Mothers

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Mit's Linctus Codeine.

CYP2D6 Genetic Variability: Ultra-Rapid Metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience of signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use Mit's Linctus Codeine.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids, including Mit's Linctus Codeine, with benzodiazepines, or other CNS depressants, including alcohol, may results in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if TUZISTRA XR is used with benzodiazepines, alcohol, or other CNS depressants.

Respiratory Depression

Codeine, one of the active ingredients in Mit's Linctus Codeine, produces dose-related respiratory depression by directly acting on brain stem respiratory centers. Codeine affects the center that controls respiratory rhythm and may produce irregular and periodic breathing. Caution should be exercised when Mit's Linctus Codeine is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilator function is depressed.

Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children has been associated with fatal respiratory depression. Exercise caution when administering Mit's Linctus Codeine because of the potential for respiratory depression. If respiratory depression occurs, discontinue Mit's Linctus Codeine and use naloxone hydrochloride when indicated to antagonize the effect and other supportive measures as necessary.

Drug Dependence

Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of Mit's Linctus Codeine. Prescribe and administer Mit's Linctus Codeine with the same degree of caution appropriate to the use of other opioid drugs.

Head Injury And Increased Intracranial Pressure

The respiratory depression effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries. The use of Mit's Linctus Codeine should be avoided in these patients.

Activities Requiring Mental Alertness

Codeine and chlorpheniramine, the active ingredients in Mit's Linctus Codeine, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Mit's Linctus Codeine. Concurrent use of Mit's Linctus Codeine with alcohol or other central nervous system depressants should be avoided because additional impairment of central nervous system performance may occur.

Obstructive Bowel Disease

Chronic use of opioids, including codeine, may result in constipation or obstructive bowel disease especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders.

Acute Abdominal Conditions

Mit's Linctus Codeine should be used with caution in patients with acute abdominal conditions since the administration of codeine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of other anticholinergics with codeine may produce paralytic ileus

Dosing

Patients should be advised to measure Mit's Linctus Codeine with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose.

Special Risk Patients

As with other opioids, Mit's Linctus Codeine should be used with caution in elderly or debilitated patients and those with asthma, persistent or chronic cough, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed, and the possibility of respiratory depression should be kept in mind.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ultra-Rapid Metabolism Of Codeine And Other Risk Factors For Life-Threatening Respiratory Depression In Children

Advise patients of the risks of respiratory depression and death with Mit's Linctus Codeine in children younger than 18 years of age. Advise patients that Mit's Linctus Codeine should not be used in children younger than 12 years of age or in a child younger than 18 years of age for treatment after tonsillectomy and/or adenoidectomy.

Overdosage

Advise patients not to increase the dose or dosing frequency of Mit's Linctus Codeine because serious adverse events such as respiratory depression may occur with overdosage.

Dosing

Administer Mit's Linctus Codeine by the oral route only. Pharmacists and prescribers should ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed.

Mit's Linctus Codeine should not be diluted with fluids or mixed together with other drugs.

Interactions With Benzodiazepines And Other Central Nervous System Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Mit's Linctus Codeine is used with benzodiazepines or other CNS depressants, including, alcohol. Because of this risk, patients should avoid concomitant use of Mit's Linctus Codeine with benzodiazepines or other CNS depressants, including alcohol.

Activities Requiring Mental Alertness

Caution patients that Mit's Linctus Codeine may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery

Controlled Substance Status/Potential For Abuse And Dependence

Caution patients that Mit's Linctus Codeine contains codeine and can produce drug dependence.

Lactation

Advise women that breastfeeding is not recommended during treatment with Mit's Linctus Codeine.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with Mit's Linctus Codeine; however, published information is available for the individual active ingredients or related active ingredients.

Codeine

Carcinogenicity studies were conducted with codeine. In 2-year studies in F344/N rats and B6C3F1 mice, codeine showed no evidence of tumorigenicity at dietary doses up to 70 and 400 mg/kg/day, respectively (approximately 10 and 30 times, respectively, the MRHDD on a mg/m² basis).

Codeine was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.

Fertility studies with codeine have not been conducted.

Chlorpheniramine

In 2-year studies in F344/N rats and B6C3F1 mice, chlorpheniramine maleate showed no evidence of tumorigenicity when administered 5 days/week at oral doses up to 30 and 50 mg/kg/day, respectively (approximately 25 and 20 times, respectively, the MRHDD on a mg/m² basis).

Chlorpheniramine maleate was not mutagenic in the in vitro bacterial reverse mutation assay or the in vitro mouse lymphoma forward mutation assay. Chlorpheniramine maleate was clastogenic in the in vitro CHO cell chromosomal aberration assay.

Chlorpheniramine maleate had no effects on fertility in rats and rabbits at oral doses approximately 25 and 30 times the MRHDD on a mg/m² basis, respectively.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Teratogenic Effects

There are no adequate and well-controlled studies of Mit's Linctus Codeine in pregnant women.

Reproductive toxicity studies have not been conducted with Mit's Linctus Codeine; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, Mit's Linctus Codeine should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Codeine

Codeine has embryolethal and fetotoxic effects in rats. In a study in which pregnant rats were dosed throughout organogenesis, a dose approximately 20 times the maximum recommended human daily dose (MRHDD; on a mg/m² basis at an oral maternal dose of 120 mg/kg/day) increased resorptions and decreased fetal weight; however, these effects occurred in the presence of maternal toxicity.

In studies in which rabbits and mice were dosed throughout organogenesis, codeine at doses approximately 9 and 45 times the MRHDD (on a mg/m² basis at 30 and 600 mg/kg/day, respectively) produced no adverse developmental effects.

Chlorpheniramine

A retrospective study found a small, but statistically significant, association between maternal use of chlorpheniramine and inguinal hernia and eye or ear anomalies in children. Other retrospective studies have found that the frequency of congenital anomalies, in general, was not increased among offspring of women who took chlorpheniramine during pregnancy. The significance of these findings to the therapeutic use of chlorpheniramine in human pregnancy is not known.

In studies with chlorpheniramine in which pregnant rats and rabbits were dosed throughout organogenesis, oral doses up to approximately 25 and 30 times the MRHDD on a mg/m² basis, respectively, produced no adverse developmental effects. However, when mice were dosed throughout pregnancy, a dose approximately 9 times the MRHDD (on a mg/m² basis at an oral maternal dose of 20 mg/kg/day) was embryolethal, and postnatal survival was decreased when dosing was continued after parturition. Embryolethality was also observed when male and female rats were dosed with approximately 9 times the MRHDD (on a mg/m² basis at an oral parental dose of 10 mg/kg/day) prior to mating.

Nonteratogenic Effects

Codeine

Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose.

Labor And Delivery

As with all opioids, administration of Mit's Linctus Codeine to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

Nursing Mothers

Risk Summary

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.

There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Mit's Linctus Codeine.

Clinical Considerations

If infants are exposed to Mit's Linctus Codeine through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Chlorpheniramine is excreted in human milk. The clinical significance is unknown; however, the anticholinergic action of chlorpheniramine may suppress lactation if taken prior to nursing.

Pediatric Use

Safety and effectiveness of Mit's Linctus Codeine in pediatric patients under 18 years of age have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death:

• Mit's Linctus Codeine is contraindicated in all children younger than 12 years of age.
• Mit's Linctus Codeine is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
• Avoid the use of Mit's Linctus Codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

Geriatric Use

Clinical efficacy and safety studies have not been conducted with Mit's Linctus Codeine. Other reported clinical experience with the individual active ingredients of Mit's Linctus Codeine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be made with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

Pharmacokinetics of Mit's Linctus Codeine has not been characterized in renal impairment subjects. Both codeine and chlorpheniramine are cleared substantially by the kidney. As such, impaired renal function could potentially lead to the risk of decreased clearance and thereby increased retention or systemic levels of both these drugs. Mit's Linctus Codeine should be used with caution in patients with severe renal impairment.

Hepatic Impairment

Pharmacokinetics of Mit's Linctus Codeine has not been characterized in hepatic impairment subjects. Both codeine and chlorpheniramine are extensively metabolized by the liver before elimination from the body. As such, impaired hepatic function could potentially lead to the risk of decreased metabolism and thereby increased systemic levels of both these drugs. TUZISTRA XR should be used with caution in patients with severe hepatic impairment.

Use of codeine, a semisynthetic opioid, may result in the following:

• Respiratory depression
• Drug dependence
• Increased intracranial pressure
• Decreased mental alertness with impaired mental and/or physical abilities
• Paralytic ileus

Use of chlorpheniramine, an antihistamine, may result in:

• Decreased mental alertness with impaired mental and/or physical abilities

Adverse reactions listed below have been reported in the literature for codeine and chlorpheniramine and may be expected to occur with Mit's Linctus Codeine. Also included are events that occurred during clinical pharmacokinetic studies (in a total of 66 healthy adult volunteers with either single or multiple dose exposure) with Mit's Linctus Codeine and judged by the investigator to be related to study treatment. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic

Allergic laryngospasm, nasal stuffiness, bronchospastic allergic reaction, hives, itching, swelling of face.

Body As A Whole

Asthenia, feeling of relaxation, redness or flushing of the face, unusual tiredness, weakness.

Cardiovascular

Fast, or slow heartbeat, hypertension, hypotension, orthostatic hypotension, palpitations, shock-like state, syncope.

Dermatological System

Skin rash, pruritus, erythema, urticaria, excessive perspiration, dermatitis.

Endocrine System

Changes in glucose utilization, decreased lactation, early menses, glycosuria, gynecomastia, hypoglycemia, increased appetite, increased libido, pheochromocytoma stimulation.

Gastrointestinal System

Nausea and vomiting, constipation, abdominal distension, abdominal pain, acute pancreatitis, dry mouth, dyspepsia, epigastric distress, loss of appetite, diarrhea, gastro-esophageal reflux, gastrointestinal hypomotility.

Genitourinary System

Ureteral spasm, urinary retention, dysuria, urinary frequency, urinary hesitancy, irritative bladder symptom.

Nervous System

Blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, false sense of well-being, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor.

Respiratory

Dryness of the pharynx and respiratory passages, laryngismus, atelectasis, wheezing, troubled breathing, respiratory depression, hiccups.

Special Senses

labyrinthitis, tinnitus, vertigo, hypermetropia, lacrimation increased, mydriasis, photophobia.

No human overdosage data are available for Mit's Linctus Codeine.

Codeine

Overdosage with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest, and death may occur.

Codeine may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Chlorpheniramine

Manifestations of chlorpheniramine overdosage may vary from central nervous system depression to stimulation. Central toxic effects are characterized by agitation, anxiety, delirium, disorientation, hallucinations, hyperactivity, sedation, and seizures. Severe overdosage may produce coma, medullary paralysis, and death. Peripheral toxicity includes hypertension, tachycardia, dysrhythmias, vasodilation, hyperpyrexia, mydriasis, urinary retention, and diminished gastrointestinal motility. Dry mouth, pharynx, bronchi, and nasal passages may be observed. Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects may predispose to hyperthermia.

An adult ingested 400 mg chlorpheniramine with no reported serious adverse effects. Toxic psychosis, a possible class effect from overdose of sedating antihistamines, has been reported with accidental overdose of chlorpheniramine.

Treatment of overdosage consists of discontinuation of Mit's Linctus Codeine together with institution of appropriate therapy.

Give primary attention to re-establishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote for respiratory depression that may result from overdosage or unusual sensitivity to opioids including codeine. Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory or circulatory depression. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug.

Hemodialysis is not routinely used to enhance the elimination of codeine or chlorpheniramine from the body. Urinary excretion of chlorpheniramine is increased when the pH of the urine is acidic; however, acid diuresis is NOT recommended to enhance elimination in overdose, as the risks of acidemia and acute tubular necrosis in patients with rhabdomyolysis far outweigh any potential benefits.

Absorption

Pharmacokinetic (PK) parameters (Mean ± SD) for Mit's Linctus Codeine (codeine polistirex and chlorpheniramine polistirex) extended-release oral suspension in fasting, healthy volunteers are shown in the table below.

Food Effect

The presence of a high-fat, high calorie meal did not significantly impact Mit's Linctus Codeine pharmacokinetics.

Distribution

Codeine has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg, indicating extensive distribution of the drug into tissues. About 7 to 25% of codeine, reportedly, is bound to plasma proteins. Codeine passes the blood brain barrier and the placental barrier. Small amounts of codeine and its metabolite, morphine, are transferred to human breast milk.

Chlorpheniramine is widely distributed throughout the tissues of the body, including the central nervous system. It reportedly has an apparent steady-state volume of distribution of approximately 3.2 L/kg in adults and children and is about 70% bound to plasma proteins. Chlorpheniramine and its metabolites likely cross the placental barrier and are excreted into human breast milk.

Metabolism

About 70-80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6glucuronide (C6G) and via O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucuronidination of codeine to C6G. CYP2D6 and CYP3A4 are the major enzymes mediating O-demethylation and N-demethylation of codeine respectively. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. Morphine and its M6 glucuronide conjugate are pharmacologically active. Whether C6G has pharmacological activity is unknown. Norcodeine and M3 glucuronide conjugate of morphine are generally not considered to be pharmacologically active.

Chlorpheniramine is rapidly and extensively metabolized via demethylation in the liver, forming mono-and didesmethyl derivatives. Oxidative metabolism of chlorpheniramine is catalyzed by CYP2D6.

Elimination

Approximately 90% of the total dose of codeine is excreted through the kidneys, of which approximately 10% is unchanged codeine. Plasma half-life of codeine was observed to be about 5 hours with Mit's Linctus Codeine.

Chlorpheniramine and its metabolites are primarily excreted through the kidneys, with large individual variation. Urinary excretion depends on urine pH and flow rate. Plasma half-life of chlorpheniramine was observed to be about 21 hours with TUZISTRA XR.