Okanorm Plus

Acetaminophen:

• Pharmacological action
• Why is Okanorm Plus (Acetaminophen) prescribed?
• Okanorm Plus dosage and administration
• Okanorm Plus side effects, adverse reactions
• Contraindications
• Using during pregnancy and breastfeeding
• Special Instructions
• Okanorm Plus (Acetaminophen) Drug Interactions
• Okanorm Plus in case of emergency / overdose
• Okanorm Plus (Acetaminophen) reviews

Pharmacological action

Okanorm Plus is an analgesic-antipyretic. It has analgesic, antipyretic and weak anti-inflammatory action. The mechanism of action is associated with inhibition of prostaglandin synthesis, the predominant influence on the thermoregulation center in the hypothalamus, enhances heat transfer.

Why is Okanorm Plus (Acetaminophen) prescribed?

Pain weak and moderate intensity of different genesis (including headache, migraine, toothache, neuralgia, myalgia, algomenorrhea; pain in trauma, burns). Fever in infectious and inflammatory diseases.

Okanorm Plus dosage and administration

Oral or rectally adults and adolescents with a body weight over 60 kg is used in a single dose of 500 mg, the multiplicity of admission - up to 4 times / Maximum duration of treatment - 5-7 days.

Maximum dose: single - 1 g, daily - 4 g.

Single dose for oral administration for children aged 6-12 years - 250-500 mg, 1-5 years - 120-250 mg, from 3 months to 1 year - 60-120 mg, up to 3 months - 10 mg / kg. Single dose rectal in children aged 6-12 years - 250-500 mg, 1-5 years - 125-250 mg.

Multiplicity - 4 at intervals of not less than 4 h. The maximum duration of treatment - 3 days.

Maximum dose: 4 single dose per day.

Okanorm Plus side effects, adverse reactions

Digestive system: rarely - dyspepsia; long-term use at high doses - hepatotoxic effects, methemoglobinemia, renal dysfunction and liver, hypochromic anemia. Hemopoietic system: rarely - thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis. Allergic reactions: rarely - skin rash, itching, hives.

Contraindications

Chronic active alcoholism, increased sensitivity to Okanorm Plus, marked disturbances of liver function and / or kidney disease, anemia, pregnancy (I term).

Using during pregnancy and breastfeeding

Okanorm Plus (Acetaminophen) crosses the placental barrier. So far, no observed adverse effects of Okanorm Plus (Acetaminophen) on the fetus in humans.

Okanorm Plus (Acetaminophen) is excreted in breast milk: the content in milk was 0.04-0.23% of the dose adopted mother.

If necessary, use of Okanorm Plus (Acetaminophen) during pregnancy and lactation (breastfeeding) should carefully weigh the potential benefits of therapy for the mother and the potential risk to the fetus or child.

In experimental studies found no embryotoxic, teratogenic and mutagenic action of Okanorm Plus (Acetaminophen).

Special Instructions

Okanorm Plus is used with caution in patients with disorders of the liver and kidneys, with benign hyperbilirubinemia, as well as in elderly patients.

With prolonged use of Okanorm Plus (Acetaminophen) is necessary to monitor patterns of peripheral blood and functional state of the liver.

Used for treatment of premenstrual tension syndrome in combination with pamabrom (diuretic, a derivative of xanthine) and mepyramine (Histamine H1-receptors blocker).

Okanorm Plus (Acetaminophen) Drug Interactions

With the simultaneous use with inducers of microsomal liver enzymes, means having hepatotoxic effect, increasing the risk of hepatotoxic action of Okanorm Plus (Acetaminophen).

With the simultaneous use of anticoagulants may be slight to moderate increase in prothrombin time.

With the simultaneous use of anticholinergics may decrease absorption of Okanorm Plus (Acetaminophen).

With the simultaneous use of oral contraceptives accelerated excretion of Okanorm Plus (Acetaminophen) from the body and may reduce its analgesic action.

With the simultaneous use with urological means reduced their effectiveness.

With the simultaneous use of activated charcoal reduced bioavailability of Okanorm Plus (Acetaminophen).

When Okanorm Plus (Acetaminophen) applied simultaneously with diazepam may decrease excretion of diazepam.

There have been reports about the possibility of enhancing mielodepression effect of zidovudine while applying with Okanorm Plus (Acetaminophen). A case of severe toxic liver injury.

Described cases of toxic effects of Okanorm Plus (Acetaminophen), while the use of isoniazid.

When applied simultaneously with carbamazepine, phenytoin, phenobarbital, primidonom decreases the effectiveness of Okanorm Plus (Acetaminophen), which is caused by an increase in its metabolism and excretion from the body. Cases of hepatotoxicity, while the use of Okanorm Plus (Acetaminophen) and phenobarbital.

In applying cholestyramine a period of less than 1 h after administration of Okanorm Plus (Acetaminophen) may decrease of its absorption.

At simultaneous application with lamotrigine moderately increased excretion of lamotrigine from the body.

With the simultaneous use of metoclopramide may increase absorption of Okanorm Plus (Acetaminophen) and its increased concentration in blood plasma.

When applied simultaneously with probenecid may decrease clearance of Okanorm Plus (Acetaminophen), with rifampicin, sulfinpyrazone - may increase clearance of Okanorm Plus (Acetaminophen) due to increasing its metabolism in the liver.

At simultaneous application of Okanorm Plus (Acetaminophen) with ethinylestradiol increases absorption of Okanorm Plus (Acetaminophen) from the gut.

Enhances the effect of indirect anticoagulants (coumarin derivatives and indandione). Antipyretic and analgesic activity of caffeine increases, reduce - rifampicin, phenobarbital and alcohol (accelerated biotransformation, inducing microsomal liver enzymes).

Okanorm Plus in case of emergency / overdose

At a reception in toxic doses (10-15 g in adults) may develop liver necrosis.

Symptoms of overdose may include: nausea, vomiting, loss of appetite, sweating, extreme tiredness, unusual bleeding or bruising, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms

Metoclopramide Hydrochloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Okanorm Plus (Metoclopramide Hydrochloride) reviews

1 INDICATIONS AND USAGE

Okanorm Plus (Metoclopramide Hydrochloride) tablets are indicated for the:

• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux in adults who fail to respond to conventional therapy.
• Relief of symptoms in adults with acute and recurrent diabetic gastroparesis.

Limitations of Use:

Okanorm Plus (Metoclopramide Hydrochloride) tablets are not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates [see Use in Specific Populations ( 8.4 ) ].

Okanorm Plus (Metoclopramide Hydrochloride) tablets are indicated for the:

• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux in adults who fail to respond to conventional therapy. (1)
• Relief of symptoms in adults with acute and recurrent diabetic gastroparesis. (1)

Limitations of Use:

Okanorm Plus (Metoclopramide Hydrochloride) tablets are not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. (1, 8.4)

2 DOSAGE AND ADMINISTRATION

Gastroesophageal Reflux

• Administer Okanorm Plus (Metoclopramide Hydrochloride) continuously or intermittently:
  • Continuous: Administer 10 to 15 mg, 30 minutes before each meal and at bedtime (maximum of 60 mg per day) for 4 to 12 weeks.
  • Intermittent: Single doses up to 20 mg prior to provoking situation.

Acute and Recurrent Diabetic Gastroparesis (2.3)

• Administer 10 mg, 30 minutes before each meal and at bedtime (maximum of 40 mg per day) for 2 to 8 weeks

Dosage Adjustment in Specific Populations (2.2, 2.3)

• For gastroesophageal reflux and acute and recurrent diabetic gastroparesis, see Full Prescribing Information for recommended dosage reductions for elderly patients, in patients with moderate or severe hepatic or renal impairment, and cytochrome P450 2D6 (CYP2D6) poor metabolizers.

2.1 Important Administration Instructions

Avoid treatment with Okanorm Plus (Metoclopramide Hydrochloride) for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

2.2 Dosage for Gastroesophageal Reflux

Okanorm Plus tablets may be administered continuously or intermittently in patients with symptomatic gastroesophageal reflux who fail to respond to conventional therapy:

Continuous Dosing

The recommended adult dosage of Okanorm Plus (Metoclopramide Hydrochloride) is 10 to 15 mg four times daily for 4 to 12 weeks. The treatment duration is determined by endoscopic response. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 60 mg.

Table 1 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

Intermittent Dosing

If symptoms only occur intermittently or at specific times of the day, administer Okanorm Plus (Metoclopramide Hydrochloride) in single dose up to 20 mg prior to the provoking situation. Consider dosage reductions for the populations and situations in Table 1.

2.3 Dosage for Acute and Recurrent Diabetic Gastroparesis

The recommended adult dosage for the treatment of acute and recurrent diabetic gastroparesis is 10 mg four times daily for 2 to 8 weeks, depending on symptomatic response. Avoid Okanorm Plus (Metoclopramide Hydrochloride) treatment for greater than 12 weeks [see Warnings and Precautions (5.1)]. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 40 mg.

Table 2 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral Okanorm Plus (Metoclopramide Hydrochloride) tablets, consider starting therapy with Okanorm Plus (Metoclopramide Hydrochloride) injection given intramuscularly or intravenously for up to 10 days injection). After patients are able to take oral therapy, switch to Okanorm Plus (Metoclopramide Hydrochloride) tablets.

3 DOSAGE FORMS AND STRENGTHS

Tablets:

• 5 mg Okanorm Plus (Metoclopramide Hydrochloride): white, round, unscored, debossed “TV” on one side and “2204” on the other side.
• 10 mg Okanorm Plus (Metoclopramide Hydrochloride): white, round, scored, debossed “TEVA” on one side and “2203” above the score on the other side.

Tablets: 5 mg and 10 mg Okanorm Plus (Metoclopramide Hydrochloride) (3)

4 CONTRAINDICATIONS

Okanorm Plus (Metoclopramide Hydrochloride) is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to Okanorm Plus (Metoclopramide Hydrochloride) [see Warnings and Precautions ( 5.1, 5.2 ) ].
• When stimulation of gastrointestinal motility might be dangerous (e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation).
• In patients with pheochromocytoma or other catecholamine-releasing paragangliomas. Okanorm Plus (Metoclopramide Hydrochloride) may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor [see Warnings and Precautions (5.5)].
• In patients with epilepsy. Okanorm Plus (Metoclopramide Hydrochloride) may increase the frequency and severity of seizures [see Adverse Reactions (6)].
• In patients with hypersensitivity to Okanorm Plus (Metoclopramide Hydrochloride). Reactions have included laryngeal and glossal angioedema and bronchospasm [see Adverse Reactions (6)].

• History of TD or dystonic reaction to Okanorm Plus (Metoclopramide Hydrochloride) (4)
• When stimulation of gastrointestinal motility might be dangerous (4)
• Pheochromocytoma, catecholamine-releasing paragangliomas (4)
• Epilepsy (4)
• Hypersensitivity to Okanorm Plus (Metoclopramide Hydrochloride) (4)

5 WARNINGS AND PRECAUTIONS

• Tardive Dyskinesia, Other Extrapyramidal Symptoms (EPS), and Neuroleptic Malignant Syndrome (NMS): Avoid concomitant use of other drugs known to cause TD/EPS/NMS and avoid use in patients with Parkinson’s Disease. If symptoms occur, discontinue Okanorm Plus (Metoclopramide Hydrochloride) and seek immediate medical attention. (5.1, 5.2, 5.3, 7.1, 7.2)
• Depression and suicidal ideation/suicide: Avoid use. (5.4)

5.1 Tardive Dyskinesia

Okanorm Plus (Metoclopramide Hydrochloride) can cause tardive dyskinesia (TD), a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetotic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with duration of treatment and total cumulative dosage. Additionally, the risk of developing TD is increased among the elderly, especially elderly women [see Use in Specific Populations (8.5)], and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with Okanorm Plus (Metoclopramide Hydrochloride) for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration (2.2, 2.3)].

Discontinue Okanorm Plus (Metoclopramide Hydrochloride) immediately in patients who develop signs and symptoms of TD. There is no known effective treatment for established cases of TD, although in some patients TD may remit, partially or completely, within several weeks to months after Okanorm Plus (Metoclopramide Hydrochloride) is withdrawn.

Okanorm Plus (Metoclopramide Hydrochloride) itself may suppress, or partially suppress, the signs of TD, thereby masking the underlying disease process. The effect of this symptomatic suppression upon the long-term course of TD is unknown. Okanorm Plus (Metoclopramide Hydrochloride) is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid Okanorm Plus (Metoclopramide Hydrochloride) in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics).

5.2 Other Extrapyramidal Symptoms

In addition to TD, Okanorm Plus may cause other extrapyramidal symptoms (EPS), parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue Okanorm Plus (Metoclopramide Hydrochloride).

• Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with Okanorm Plus (Metoclopramide Hydrochloride) dosages of 30 mg to 40 mg daily. Such reactions occurred more frequently in adults less than 30 years of age and at higher than recommended dosages. EPS occurred more frequently in pediatric patients compared to adults (metoclopramide is not approved for use in pediatric patients). Symptoms can occur in the first 24 to 48 hours after starting Okanorm Plus (Metoclopramide Hydrochloride). Symptoms included involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus. Rarely, dystonic reactions were present as stridor and dyspnea, possibly due to laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse reactions. Avoid Okanorm Plus (Metoclopramide Hydrochloride) in patients receiving other drugs that can cause EPS (e.g., antipsychotics).
• Parkinsonian symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies) have occurred after starting Okanorm Plus (Metoclopramide Hydrochloride), more commonly within the first 6 months, but also after longer periods. Symptoms generally have subsided within 2 to 3 months after discontinuation of Okanorm Plus (Metoclopramide Hydrochloride). Avoid Okanorm Plus (Metoclopramide Hydrochloride) in patients with Parkinson’s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with Okanorm Plus (Metoclopramide Hydrochloride) for more than 12 weeks [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].
• Motor restlessness (akathisia) has developed and consisted of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. If symptoms resolve, consider restarting at a lower dosage.

5.3 Neuroleptic Malignant Syndrome

Okanorm Plus (Metoclopramide Hydrochloride) may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with Okanorm Plus (Metoclopramide Hydrochloride) overdosage and concomitant treatment with another drug associated with NMS. Avoid Okanorm Plus (Metoclopramide Hydrochloride) in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics.

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients with such symptoms should be evaluated immediately.

In the diagnostic evaluation, consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome, and primary central nervous system pathology.

Management of NMS includes:

• Immediate discontinuation of Okanorm Plus (Metoclopramide Hydrochloride) and other drugs not essential to concurrent therapy [see Drug Interactions (7.1)].
• Intensive symptomatic treatment and medical monitoring.
• Treatment of any concomitant serious medical problems for which specific treatments are available.

5.4 Depression

Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal ideation and suicide. Avoid Okanorm Plus use in patients with a history of depression.

5.5 Hypertension

Okanorm Plus (Metoclopramide Hydrochloride) may elevate blood pressure. In one study in hypertensive patients, intravenously administered Okanorm Plus (Metoclopramide Hydrochloride) was shown to release catecholamines; hence, avoid use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see Drug Interactions (7.1)].

There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. Okanorm Plus (Metoclopramide Hydrochloride) is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue Okanorm Plus (Metoclopramide Hydrochloride) in any patient with a rapid rise in blood pressure.

5.6 Fluid Retention

Because Okanorm Plus produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of developing fluid retention and volume overload. Discontinue Okanorm Plus (Metoclopramide Hydrochloride) if any of these adverse reactions occur.

5.7 Hyperprolactinemia

As with other dopamine D₂ receptor antagonists, Okanorm Plus (Metoclopramide Hydrochloride) elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including Okanorm Plus (Metoclopramide Hydrochloride).

Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D₂ receptor antagonists and tumorigenesis in humans [see Nonclinical Toxicology ( 13.1 ) ].

5.8 Effects of the Ability to Drive and Operate Machinery

Okanorm Plus (Metoclopramide Hydrochloride) may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. Concomitant use of central nervous system (CNS) depressants or drugs associated with EPS may increase this effect (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics). Avoid Okanorm Plus (Metoclopramide Hydrochloride) or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)].

6 ADVERSE REACTIONS

The following adverse reactions are described, or described in greater detail, in other sections of the labeling:

• Tardive dyskinesia [see Boxed Warning and Warnings and Precautions (5.1)]
• Other extrapyramidal effects [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Depression [see Warnings and Precautions (5.4)]
• Hypertension [see Warnings and Precautions (5.5)]
• Fluid retention [see Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Effects on the ability to drive and operate machinery [see Warnings and Precautions (5.8)]

The following adverse reactions have been identified from clinical studies or postmarketing reports of Okanorm Plus (Metoclopramide Hydrochloride). Because these reactions are 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.

The most common adverse reactions (in approximately 10% of patients receiving 10 mg of Okanorm Plus (Metoclopramide Hydrochloride) four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of Okanorm Plus (Metoclopramide Hydrochloride) administration.

Adverse reactions, especially those involving the nervous system, occurred after stopping Okanorm Plus (Metoclopramide Hydrochloride) including dizziness, nervousness, and headaches.

Central Nervous System Disorders

• Tardive dyskinesia, acute dystonic reactions, drug-induced parkinsonism, akathisia, and other extrapyramidal symptoms
• Convulsive seizures
• Hallucinations
• Restlessness, drowsiness, fatigue, and lassitude occurred in approximately 10% of patients who received 10 mg four times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurred less frequently.
• Neuroleptic malignant syndrome, serotonin syndrome (in combination with serotonergic agents).

Endocrine Disorders: Fluid retention secondary to transient elevation of aldosterone. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia

Cardiovascular Disorders: Acute congestive heart failure, possible atrioventricular block, hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention

Gastrointestinal Disorders: Nausea, bowel disturbances (primarily diarrhea)

Hepatic Disorders: Hepatotoxicity, characterized by, e.g., jaundice and altered liver function tests, when Okanorm Plus (Metoclopramide Hydrochloride) was administered with other drugs with known hepatotoxic potential

Renal and Urinary Disorders: Urinary frequency, urinary incontinence

Hematologic Disorders: Agranulocytosis, neutropenia, leukopenia, methemoglobinemia, sulfhemoglobinemia

Hypersensitivity Reactions: Bronchospasm (especially in patients with a history of asthma), urticaria; rash; angioedema, including glossal or laryngeal edema

Eye Disorders: Visual disturbances

Metabolism Disorders: Porphyria

• Most common adverse reactions (> 10%) are restlessness, drowsiness, fatigue, and lassitude. (6)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

• Antipsychotics: Potential for additive effects, including TD, EPS, and NMS; avoid concomitant use.
• CNS depressants: Increased risk of CNS depression. Avoid concomitant use and monitor for adverse reactions. (7.1)
• Strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine): See Full Prescribing Information for recommended dosage reductions. (2.2, 2.3, 7.1)
• MAO inhibitors: Increased risk of hypertension; avoid concomitant use. (5.5, 7.1)
• Additional drug interactions: See Full Prescribing Information. (7.1, 7.2)

7.1 Effects of Other Drugs on Okanorm Plus (Metoclopramide Hydrochloride)

Table 3 displays the effects of other drugs on Okanorm Plus (Metoclopramide Hydrochloride).

7.2 Effects of Okanorm Plus on Other Drugs

Table 4 displays the effects of Okanorm Plus (Metoclopramide Hydrochloride) on other drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report an increased risk of adverse pregnancy-related outcomes with use of Okanorm Plus during pregnancy.

There are potential risks to the neonate following exposure in utero to Okanorm Plus (Metoclopramide Hydrochloride) during delivery [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of Okanorm Plus (Metoclopramide Hydrochloride) to pregnant rats and rabbits at exposures about 6 and 12 times the maximum recommended human dose (MRHD) [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Okanorm Plus (Metoclopramide Hydrochloride) crosses the placental barrier and may cause extrapyramidal signs and methemoglobinemia in neonates with maternal administration during delivery. Monitor neonates for extrapyramidal signs [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)].

Data

Animal Data

Reproduction studies have been performed following administration of oral Okanorm Plus (Metoclopramide Hydrochloride) during organogenesis in pregnant rats at about 6 times the MRHD calculated on body surface area and in pregnant rabbits at about 12 times the MRHD calculated on body surface area. No evidence of adverse developmental effects due to Okanorm Plus (Metoclopramide Hydrochloride) were observed.

8.2 Lactation

Risk Summary

Limited published data report the presence of Okanorm Plus (Metoclopramide Hydrochloride) in human milk in variable amounts. Breastfed infants exposed to Okanorm Plus (Metoclopramide Hydrochloride) have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation [see Data]. Okanorm Plus (Metoclopramide Hydrochloride) elevates prolactin levels [see Warnings and Precautions (5.7)]; however, the published data are not adequate to support drug effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Okanorm Plus (Metoclopramide Hydrochloride) and any potential adverse effects on the breastfed child from Okanorm Plus (Metoclopramide Hydrochloride) or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding neonates because Okanorm Plus (Metoclopramide Hydrochloride) may cause extrapyramidal signs (dystonias) and methemoglobinemia [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)].

Data

In published clinical studies, the estimated amount of Okanorm Plus (Metoclopramide Hydrochloride) received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of Okanorm Plus (Metoclopramide Hydrochloride) received by infants from breast milk ranged from 6 to 24 mcg/kg/day in early puerperium (3 to 9 days postpartum) and from 1 to 13 mcg/kg/day at 8 to 12 weeks postpartum.

8.4 Pediatric Use

Okanorm Plus is not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of Okanorm Plus (Metoclopramide Hydrochloride) in pediatric patients have not been established.

Dystonias and other extrapyramidal symptoms associated with Okanorm Plus (Metoclopramide Hydrochloride) are more common in pediatric patients than in adults [see Warnings and Precautions (5.1, 5.2)]. In addition, neonates have reduced levels of NADH-cytochrome b₅ reductase, making them more susceptible to methemoglobinemia, a possible adverse reaction of Okanorm Plus (Metoclopramide Hydrochloride) use in neonates [see Use in Specific Populations (8.8)].

8.5 Geriatric Use

Okanorm Plus (Metoclopramide Hydrochloride) is known to be substantially excreted by the kidney, and the risk of adverse reactions, including tardive dyskinesia (TD), may be greater in patients with impaired renal function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Elderly patients are more likely to have decreased renal function and may be more sensitive to the therapeutic or adverse effects of Okanorm Plus (Metoclopramide Hydrochloride); therefore, consider a reduced dosage of Okanorm Plus (Metoclopramide Hydrochloride) in elderly patients [see Boxed Warning, Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

8.6 Renal Impairment

The clearance of Okanorm Plus is decreased and the systemic exposure is increased in patients with moderate to severe renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions. Reduce the Okanorm Plus (Metoclopramide Hydrochloride) dosage in patients with moderate and severe renal impairment (creatinine clearance less than or equal to 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic Okanorm Plus (Metoclopramide Hydrochloride) clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in Okanorm Plus (Metoclopramide Hydrochloride) blood concentrations increases the risk of adverse reactions. There is no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce Okanorm Plus (Metoclopramide Hydrochloride) dosage in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [see Dosage and Administration (2.2, 2.3)]. There is no dosage adjustment required for patients with mild hepatic impairment (Child-Pugh A).

In addition, Okanorm Plus (Metoclopramide Hydrochloride), by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment [see Warnings and Precautions (5.6)].

Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.

8.8 NADH-Cytochrome b₅ Reductase Deficiency

Metoclopramide-treated patients with NADH-cytochrome b₅ reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase deficiency with metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal [see Overdosage (10)].

8.9 CYP2D6 Poor Metabolizers

Okanorm Plus (Metoclopramide Hydrochloride) is a substrate of CYP2D6. The elimination of Okanorm Plus (Metoclopramide Hydrochloride) may be slowed in patients who are CYP2D6 poor metabolizers (compared to patients who are CYP2D6 intermediate, extensive, or ultra-rapid metabolizers); possibly increasing the risk of dystonic and other adverse reactions to Okanorm Plus (Metoclopramide Hydrochloride) [see Clinical Pharmacology (12.3)]. Reduce the Okanorm Plus (Metoclopramide Hydrochloride) dosage in patients who are poor CYP2D6 metabolizers [see Dosage and Administration (2.2, 2.3)].

10 OVERDOSAGE

Manifestations of Okanorm Plus (Metoclopramide Hydrochloride) overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with Okanorm Plus (Metoclopramide Hydrochloride) use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with Okanorm Plus (Metoclopramide Hydrochloride) overdose and concomitant treatment with another drug associated with NMS [see Warnings and Precautions (5.1, 5.2, 5.3)].

There are no specific antidotes for Okanorm Plus (Metoclopramide Hydrochloride) overdosage. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may be fatal.

Hemodialysis and continuous ambulatory peritoneal dialysis do not remove significant amounts of Okanorm Plus (Metoclopramide Hydrochloride).

11 DESCRIPTION

Okanorm Plus (Metoclopramide Hydrochloride) hydrochloride, USP, the active ingredient of Okanorm Plus (Metoclopramide Hydrochloride) tablets, is a dopamine-2 receptor antagonist. Okanorm Plus (Metoclopramide Hydrochloride) hydrochloride (metoclopramide monohydrochloride monohydrate) is a white or practically white, crystalline, odorless or practically odorless powder. It is very soluble in water, freely soluble in alcohol, sparingly soluble in chloroform and practically insoluble in ether. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate. Its structural formula is as follows:

C₁₄H₂₂ClN₃O₂-HCl-H₂O M.W. 354.3

Okanorm Plus (Metoclopramide Hydrochloride) tablets are for oral administration. Okanorm Plus (Metoclopramide Hydrochloride) tablets are available in 5 mg and 10 mg tablets.

• Each Okanorm Plus (Metoclopramide Hydrochloride) tablet, 5 mg contains 5 mg Okanorm Plus (Metoclopramide Hydrochloride) (equivalent to 5.91 mg of Okanorm Plus (Metoclopramide Hydrochloride) hydrochloride, USP).
• Each Okanorm Plus (Metoclopramide Hydrochloride) tablet, 10 mg contains 10 mg Okanorm Plus (Metoclopramide Hydrochloride) (equivalent to 11.82 mg of Okanorm Plus (Metoclopramide Hydrochloride) hydrochloride, USP).

Inactive Ingredients

Corn starch, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Okanorm Plus stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of Okanorm Plus (Metoclopramide Hydrochloride) in the treatment of gastroesophageal reflux and acute and recurrent diabetic gastroparesis has not been fully established. It seems to sensitize tissues to the action of acetylcholine. The effect of Okanorm Plus (Metoclopramide Hydrochloride) on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.

Okanorm Plus (Metoclopramide Hydrochloride) increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder.

12.2 Pharmacodynamics

Gastroesophageal Reflux

In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of Okanorm Plus (Metoclopramide Hydrochloride) produced dose-related increases in LESP. Effects began at about 5 mg and increased through 20 mg. The increase in LESP from a 5 mg dose lasted about 45 minutes and that of 20 mg lasted between 2 and 3 hours. Increased rate of stomach emptying was observed with single oral doses of 10 mg.

12.3 Pharmacokinetics

Absorption

Relative to an intravenous dose of 20 mg, the absolute bioavailability of oral Okanorm Plus (Metoclopramide Hydrochloride) is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. Peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. Similar time to peak was observed after individual doses at steady state.

In a single dose study of 12 subjects, the area under the drug concentration-time curve increased linearly with doses from 20 to 100 mg (5 times the maximum recommended single dose). Peak concentrations increased linearly with dose; time to peak concentrations remained the same; whole body clearance was unchanged; and the elimination rate remained the same. The mean elimination half-life in subjects with normal renal function was 5 to 6 hours. Linear kinetic processes adequately describe the absorption and elimination of Okanorm Plus (Metoclopramide Hydrochloride).

Distribution

Okanorm Plus (Metoclopramide Hydrochloride) is not extensively bound to plasma proteins (about 30%). The whole body volume of distribution is high (about 3.5 L/kg), which suggests extensive distribution of drug to the tissues.

Elimination

Metabolism: Okanorm Plus (Metoclopramide Hydrochloride) undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. Monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by CYP2D6, an enzyme subject to genetic variability [see Dosage and Administration (2.2, 2.3), Use in Specific Populations (8.9)].

Excretion: Approximately 85% of the radioactivity of an orally administered dose appeared in the urine within 72 hours. After oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free Okanorm Plus (Metoclopramide Hydrochloride) in urine within 36 hours.

Specific Populations

Patients with Renal Impairment: In a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (ESRD) requiring dialysis), the systemic exposure (AUC) of Okanorm Plus (Metoclopramide Hydrochloride) in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of Okanorm Plus (Metoclopramide Hydrochloride) in patients with ESRD on dialysis was about 3.5-fold the AUC in subjects with normal renal function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: In a group of 8 patients with severe hepatic impairment (Child-Pugh C), the average Okanorm Plus (Metoclopramide Hydrochloride) clearance was reduced by approximately 50% compared to patients with normal hepatic function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.7)].

Drug Interaction Studies

Effect of Okanorm Plus (Metoclopramide Hydrochloride) on CYP2D6 Substrates

Although in vitro studies suggest that Okanorm Plus (Metoclopramide Hydrochloride) can inhibit CYP2D6, Okanorm Plus (Metoclopramide Hydrochloride) is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.

Effect of CYP2D6 Inhibitors on Okanorm Plus (Metoclopramide Hydrochloride)

In healthy subjects, 20 mg of Okanorm Plus (Metoclopramide Hydrochloride) and 60 mg of fluoxetine (a strong CYP2D6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. The patients who received concomitant Okanorm Plus (Metoclopramide Hydrochloride) and fluoxetine had a 40% and 90% increase in Okanorm Plus (Metoclopramide Hydrochloride) C_max and AUC_0-∞, respectively, compared to patients who received Okanorm Plus (Metoclopramide Hydrochloride) alone [see Drug Interactions (7.1)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 77-week study was conducted in rats with oral Okanorm Plus (Metoclopramide Hydrochloride) doses up to 40 mg/kg/day (about six times the maximum recommended human dose on body surface area basis). Okanorm Plus (Metoclopramide Hydrochloride) elevated prolactin levels and the elevation persisted during chronic administration. An increase in mammary neoplasms was found in rodents after chronic administration of Okanorm Plus (Metoclopramide Hydrochloride) [see Warnings and Precautions (5.7)]. In a rat model for assessing the tumor promotion potential, a 2-week oral treatment with Okanorm Plus (Metoclopramide Hydrochloride) at a dose of 260 mg/kg/day (about 35 times the maximum recommended human dose based on body surface area) enhanced the tumorigenic effect of N-nitrosodiethylamine.

Mutagenesis

Okanorm Plus (Metoclopramide Hydrochloride) was positive in the in vitro Chinese hamster lung cell/HGPRT forward mutation assay for mutagenic effects and in the in vitro human lymphocyte chromosome aberration assay for clastogenic effects. It was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis assay with rat and human hepatocytes, and the in vivo rat micronucleus assay.

Impairment of Fertility

Okanorm Plus (Metoclopramide Hydrochloride) at intramuscular doses up to 20 mg/kg/day (about three times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each white, round, unscored, debossed “TV” on one side and “2204” on the other side, compressed Okanorm Plus (Metoclopramide Hydrochloride) tablet, USP contains Okanorm Plus (Metoclopramide Hydrochloride) hydrochloride, USP equivalent to 5 mg Okanorm Plus (Metoclopramide Hydrochloride). Available in bottles of 100 (NDC 0093-2204-01) and 500 (NDC 0093-2204-05).

Each white, round, scored, debossed “TEVA” on one side and “2203” above the score on the other side, compressed Okanorm Plus (Metoclopramide Hydrochloride) tablet, USP contains Okanorm Plus (Metoclopramide Hydrochloride) hydrochloride, USP equivalent to 10 mg Okanorm Plus (Metoclopramide Hydrochloride). Available in bottles of 100 (NDC 0093-2203-01), 500 (NDC 0093-2203-05), and 1000 (NDC 0093-2203-10).

Dispense in a tight, light-resistant container. Store tablets at 20° to 25°C (68° to 77°F).

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

17 PATIENT COUNSELING INFORMATION

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

Inform patients or their caregivers that Okanorm Plus (Metoclopramide Hydrochloride) can cause serious adverse reactions. Instruct patients to discontinue Okanorm Plus (Metoclopramide Hydrochloride) and contact a healthcare provider immediately if the following serious reactions occur:

• Tardive dyskinesia and other extrapyramidal reactions [see Warnings and Precautions (5.1, 5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Depression and/or possible suicidal ideation [see Warnings and Precautions (5.4)]

Inform patients or their caregivers that concomitant treatment with numerous other medications can precipitate or worsen serious adverse reactions such as tardive dyskinesia or other extrapyramidal reactions, neuroleptic malignant syndrome, and CNS depression [see Drug Interactions (7.1, 7.2)]. Explain that the prescriber of any other medication must be made aware that the patient is taking Okanorm Plus (Metoclopramide Hydrochloride).

Inform patients or their caregivers that Okanorm Plus (Metoclopramide Hydrochloride) can cause drowsiness or dizziness, or otherwise impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle [see Warnings and Precautions (5.8)].

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. Q 8/2017

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. D 8/2017

NDC 0093-2204-01

Okanorm Plus (Metoclopramide Hydrochloride)

Tablets, USP

5mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

NDC 0093-2203-01

Okanorm Plus (Metoclopramide Hydrochloride)

Tablets, USP

10 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA