Sedoril-DCP

Chlorpheniramine Maleate:

• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions? comments?
• Sedoril-DCP (Chlorpheniramine Maleate) reviews

Drug Facts

Uses

temporarily relieves these symptoms due to the common cold, hay fever (allergic rhinitis) or other upper respiratory allergies

• runny nose
• sneezing
• itching of the nose or throat
• itchy, watery eyes
• nasal congestion
• reduces swelling of nasal passages

Warnings

Do not exceed recommended dosage.

Do not use this product in a child who is

• now taking a prescription monoamine oxidase inhibitor (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your child's prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Ask a doctor before use if a child has

• a breathing problem such as chronic bronchitis
• glaucoma
• heart disease
• high blood pressure
• thyroid disease
• diabetes mellitus

Ask a doctor before use if a child is taking sedatives or tranquilizers

When using this product

• excitability may occur, especially in children
• may cause drowsiness
• sedatives and tranquilizers may increase drowsiness effect

Stop use and ask a doctor if

• nervousness, dizziness, or sleeplessness occur
• new symptoms occur

Keep out of reach of children. In case of accidental overdose, seek professional help or contact a Poison Control Center immediately.

Directions

Do not exceed recommended dosage.

Other information

Store at 59°-86°F (15°-30°C)

Inactive ingredients

Applesauce Flavor, Citric Acid, FD&C Blue #1, FD&C Yellow #6, Glycerin, Methyl Paraben, Potassium Citrate, Potassium Sorbate, Propyl Paraben, Propylene Glycol, Purified Water, Sucralose

Questions? Comments?

Call 1-800-543-9560

Rev. 05/11

E

NEW

FORMULA

NDC 00485-0096-02

Sedoril-DCP (Chlorpheniramine Maleate)

Pediatric Drops

Antihistamine ▪ Nasal Decongestant

Sugar Free ▪ Alcohol Free ▪ Gluten Free

FOR PROFESSIONAL USE ONLY

Each 1 mL for oral administration

contains:

Sedoril-DCP (Chlorpheniramine Maleate) Maleate

2 mg

Phenylephrine HCl

5 mg

APPLESAUCE FLAVOR

Tamper evident by foil seal under cap.

Do not use if foil seal is broken or missing.

Manufactured for:

EDWARDS

Pharmaceuticals, Inc.

Ripley, MS 38663

2 fl. oz. (60 mL)

Dextromethorphan Hydrochloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• How supplied/storage and handling
• Patient counseling information
• Sedoril-DCP (Dextromethorphan Hydrochloride) reviews

1 INDICATIONS AND USAGE

Sedoril-DCP (Dextromethorphan Hydrochloride) is indicated for the treatment of pseudobulbar affect (PBA).

PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury.

Sedoril-DCP (Dextromethorphan Hydrochloride) is a combination product containing Sedoril-DCP (Dextromethorphan Hydrochloride) hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and quinidine sulfate (a CYP450 2D6 inhibitor) indicated for the treatment of pseudobulbar affect (PBA). (1)

2 DOSAGE AND ADMINISTRATION

• Starting dose: one capsule daily by mouth for 7 days.
  

• Maintenance dose: After 7 days, 1 capsule every 12 hours. (2.1)

2.1 Recommended Dose

The recommended starting dose of Sedoril-DCP (Dextromethorphan Hydrochloride) is one capsule daily by mouth for the initial seven days of therapy. On the eighth day of therapy and thereafter, the daily dose should be a total of two capsules a day, given as one capsule every 12 hours.

The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA occurs in some patients.

3 DOSAGE FORMS AND STRENGTHS

Sedoril-DCP (Dextromethorphan Hydrochloride) capsules contain 20 mg Sedoril-DCP (Dextromethorphan Hydrochloride) hydrobromide and 10 mg quinidine sulfate in a brick red gelatin capsule with “DMQ 20-10” printed in white ink on the capsule.

Capsules: Sedoril-DCP (Dextromethorphan Hydrochloride) hydrobromide 20 mg/quinidine sulfate 10 mg. (3)

4 CONTRAINDICATIONS

• Concomitant use with quinidine, quinine, or mefloquine.
  

• Patients with a history of quinidine, quinine or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reactions. (4.2)
  

• Patients with known hypersensitivity to Sedoril-DCP (Dextromethorphan Hydrochloride). (4.2)
  

• Use with an MAOI or within 14 days of stopping an MAOI. Allow 14 days after stopping Sedoril-DCP (Dextromethorphan Hydrochloride) before starting an MAOI. (4.3)
  

• Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure. (4.4)
  

• Complete atrioventricular (AV) block without implanted pacemaker, or patients at high risk of complete AV block. (4.4)
  

• Concomitant use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide). (4.4)

4.1 Quinidine and Related D rugs

Sedoril-DCP (Dextromethorphan Hydrochloride) contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine.

4.2 Hypersensitivity

Sedoril-DCP is contraindicated in patients with a history of Sedoril-DCP (Dextromethorphan Hydrochloride), quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome. Sedoril-DCP (Dextromethorphan Hydrochloride) is also contraindicated in patients with a known hypersensitivity to Sedoril-DCP (Dextromethorphan Hydrochloride) (e.g. rash, hives) [ see Warnings and Precautions ( 5.1 ) ].

4.3 MAOIs

Sedoril-DCP (Dextromethorphan Hydrochloride) is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping Sedoril-DCP (Dextromethorphan Hydrochloride) before starting an MAOI [ see Drug Interactions ( 7.1 ) ].

4.4 Cardiovascular

Sedoril-DCP (Dextromethorphan Hydrochloride) is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, and in patients with heart failure [ see Warnings and Precautions ( 5.3 ) ].

Sedoril-DCP (Dextromethorphan Hydrochloride) is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide), as effects on QT interval may be increased [ see Drug Interactions ( 7.2 ) ].

Sedoril-DCP (Dextromethorphan Hydrochloride) is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block.

5 WARNINGS AND PRECAUTIONS

• Thrombocytopenia or other hypersensitivity reactions: Discontinue if occurs.
  

• Hepatitis: Discontinue if occurs. (5.2)
  

• QT Prolongation: Monitor ECG if concomitant use of drugs that prolong QT interval cannot be avoided or if concomitant CYP3A4 inhibitors used. (5.3)
  

• Left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD): Monitor ECG in patients with LVH or LVD. (5.3)
  

• CYP2D6 substrate: Sedoril-DCP (Dextromethorphan Hydrochloride) inhibits CYP2D6. Accumulation of parent drug and/or failure of metabolite formation may decrease safety and/or efficacy of concomitant CYP2D6 metabolized drugs. Adjust dose of CYP2D6 substrate or use alternative treatment when clinically indicated. (5.4,12.4)
  

• Dizziness: Take precautions to reduce falls. (5.5)
  

• Serotonin syndrome: Use of Sedoril-DCP (Dextromethorphan Hydrochloride) with selective serotonin reuptake inhibitor (SSRIs) or tricyclic antidepressants increases the risk. Discontinue if occurs. (5.6,7.4)
  

• Anticholinergic effects of quinidine: Monitor for worsening in myasthenia gravis and other sensitive conditions. (5.7)

5.1 Thrombocytopenia and Other Hypersensitivity Reactions

Quinidine can cause immune-mediated thrombocytopenia that can be severe or fatal. Non-specific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, can precede or occur with thrombocytopenia. NUEDEXTA should be discontinued immediately if thrombocytopenia occurs, unless the thrombocytopenia is clearly not drug-related, as continued use increases the risk for fatal hemorrhage. Likewise, Sedoril-DCP (Dextromethorphan Hydrochloride) should not be restarted in sensitized patients, because more rapid and more severe thrombocytopenia than the original episode can occur. Sedoril-DCP (Dextromethorphan Hydrochloride) should not be used if immune-mediated thrombocytopenia from structurally related drugs, including quinine and mefloquine is suspected, as cross-sensitivity can occur. Quinidine-associated thrombocytopenia usually, but not always, resolves within a few days of discontinuation of the sensitizing drug.

Quinidine has also been associated with a lupus-like syndrome involving polyarthritis, sometimes with a positive antinuclear antibody test. Other associations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevation in serum levels of skeletal-muscle enzymes, and pneumonitis.

5.2 Hepatotoxicity

Hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Fever may be a presenting symptom, and thrombocytopenia or other signs of hypersensitivity may also occur. Most cases remit when quinidine is withdrawn.

5.3 Cardiac Effects

Sedoril-DCP causes dose-dependent QTc prolongation [ see Clinical Pharmacology ( 12.2 ) ]. QT prolongation can cause torsades de pointes-type ventricular tachycardia, with the risk increasing as the degree of prolongation increases. When initiating Sedoril-DCP (Dextromethorphan Hydrochloride) in patients at risk of QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3-4 hours after the first dose. This includes patients concomitantly taking/initiating drugs that prolong the QT interval or that are strong or moderate CYP3A4 inhibitors, and patients with left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD). LVH and LVD are more likely to be present in patients with chronic hypertension, known coronary artery disease, or history of stroke. LVH and LVD can be diagnosed utilizing echocardiography or another suitable cardiac imaging modality.

Strong and moderate CYP3A inhibitors include, but are not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil.

Reevaluate ECG if risk factors for arrhythmia change during the course of treatment with Sedoril-DCP (Dextromethorphan Hydrochloride). Risk factors include concomitant use of drugs associated with QT prolongation, electrolyte abnormality (hypokalemia, hypomagnesemia), bradycardia, and family history of QT abnormality. Hypokalemia and hypomagnesemia should be corrected prior to initiation of therapy with Sedoril-DCP (Dextromethorphan Hydrochloride), and should be monitored during treatment.

If patients taking Sedoril-DCP (Dextromethorphan Hydrochloride) experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., syncope or palpitations, Sedoril-DCP (Dextromethorphan Hydrochloride) should be discontinued and the patient further evaluated.

5.4 Concomitant use of CYP2D6 Substrates

The quinidine in Sedoril-DCP (Dextromethorphan Hydrochloride) inhibits CYP2D6 in patients in whom CYP2D6 is not otherwise genetically absent or its activity otherwise pharmacologically inhibited [ see Warnings and Precautions ( 5.8 ) and Clinical Pharmacology ( 12.3 ), ( 12.5 ) ]. Because of this effect on CYP2D6, accumulation of parent drug and/or failure of active metabolite formation may decrease the safety and/or the efficacy of drugs used concomitantly with Sedoril-DCP (Dextromethorphan Hydrochloride) that are metabolized by CYP2D6 [ see Drug Interactions ( 7.5 ) ].

5.5 Dizziness

Sedoril-DCP may cause dizziness [ see Adverse Reactions ( 6.1 ) ]. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls. In a controlled trial of Sedoril-DCP (Dextromethorphan Hydrochloride), 10% of patients on Sedoril-DCP (Dextromethorphan Hydrochloride) and 5% on placebo experienced dizziness.

5.6 Serotonin Syndrome

When used with SSRIs (such as fluoxetine) or tricyclic antidepressants (such as clomipramine and imipramine), Sedoril-DCP (Dextromethorphan Hydrochloride) may cause “serotonin syndrome”, with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [ see Drug Interactions ( 7.4 ), Overdosage ( 10 ) ].

5.7 Anticholinergic Effects of Q uinidine

Monitor for worsening clinical condition in myasthenia gravis and other conditions that may be adversely affected by anticholinergic effects.

5.8 CYP2D6 Poor Metabolizers

The quinidine component of Sedoril-DCP (Dextromethorphan Hydrochloride) is intended to inhibit CYP2D6 so that higher exposure to Sedoril-DCP (Dextromethorphan Hydrochloride) can be achieved compared to when Sedoril-DCP (Dextromethorphan Hydrochloride) is given alone [ see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 ), ( 12.5 ) ]. Approximately 7-10% of Caucasians and 3-8% of African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs). The quinidine component of Sedoril-DCP (Dextromethorphan Hydrochloride) is not expected to contribute to the effectiveness of Sedoril-DCP (Dextromethorphan Hydrochloride) in PMs, but adverse events of the quinidine are still possible. In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat with Sedoril-DCP (Dextromethorphan Hydrochloride).

6 ADVERSE REACTIONS

A total of 946 patients participated in four Phase 3 controlled and uncontrolled PBA studies and received at least one dose of the combination product of dextromethorphan/quinidine in various strengths at the recommended or higher than the recommended dose. Of those patients, 393 patients were exposed for at least 180 days and 294 patients were exposed for at least one year. Median exposure was 168 days.

Controlled trials enrolled only patients with either ALS or MS. Uncontrolled studies enrolled 136 patients with PBA secondary to a wide variety of underlying neurological conditions including stroke and traumatic brain injury (23 patients). Consequently, patients with other underlying neurologic diseases may experience other adverse reactions not described below.

The most common adverse reactions (incidence of ≥ 3% and two-fold greater than placebo) in patients taking Sedoril-DCP (Dextromethorphan Hydrochloride) are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Avanir Pharmaceuticals, Inc. at 1-855-4NUEDEX (468-3339) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

A 12-week, placebo-controlled study evaluated Sedoril-DCP (Dextromethorphan Hydrochloride) (dextromethorphan 20 mg/quinidine 10 mg) (N=107) and a 30 mg dextromethorphan/10 mg quinidine combination (N=110) compared to placebo (N=109). Approximately 60% of patients had ALS and 40% had MS. Patients were 25 to 80 years of age, with a mean age of approximately 51 years. Three (3) ALS patients in each drug treatment arm and 1 ALS patient in the placebo arm died during the 12-week placebo-control period. All deaths were consistent with the natural progression of ALS.

Adverse Reactions Leading to Discontinuation

The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) that led to discontinuation with the 20 mg dextromethorphan/10 mg quinidine twice daily dose were muscle spasticity (3%), respiratory failure (1%), abdominal pain (2%), asthenia (2%), dizziness (2%), fall (1%), and muscle spasms (2%).

Most Common Adverse Reactions

Adverse drug reactions that occurred in ≥ 3% of patients receiving the 20 mg dextromethorphan/10 mg quinidine twice daily dose, and at an incidence of ≥ 2 times placebo in short-term clinical trials in ALS and MS are provided in Table 1.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

6.2 Long-Term Exposure with Sedoril-DCP

The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials.

6.3 Safety Experience of Individual Components

The following adverse reactions have been reported with the use of the individual components of Sedoril-DCP (Dextromethorphan Hydrochloride), Sedoril-DCP (Dextromethorphan Hydrochloride) and quinidine, from post-marketing experience. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Sedoril-DCP (Dextromethorphan Hydrochloride)

Drowsiness, dizziness, nervousness or restlessness, nausea, vomiting, and stomach pain.

Quinidine

Cinchonism is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose of several hundred milligrams. Cinchonism is characterized by nausea, vomiting, diarrhea, headache, tinnitus, hearing loss, vertigo, blurred vision, diplopia, photophobia, confusion, and delirium.

Convulsions, apprehension, and ataxia have been reported with quinidine therapy, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion in patients being treated for cardiovascular indications. Acute psychotic reactions have been reported to follow the first dose of quinidine, but these reactions appear to be extremely rare. Other adverse reactions occasionally reported with quinidine therapy include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, keratopathy, and abnormalities of skin pigmentation.

7 DRUG INTERACTIONS

• Desipramine: Exposure increases 8-fold. Reduce desipramine dose and adjust based on clinical response.
  

• Paroxetine: Exposure increases 2-fold. Reduce paroxetine dose and adjust based on clinical response. (7.5,12.4)
  

• Digoxin: Increased digoxin substrate plasma concentration may occur. (7.6)

7.1 MAOIs

Do not use Sedoril-DCP (Dextromethorphan Hydrochloride) with monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days [ see Contraindications ( 4.3 ) ].

7.2 Drugs that Prolong QT and are Metabolized by CYP2D6

Do not use with drugs that both prolong QT interval and are metabolized by CYP2D6 [ see Contraindications ( 4.4 ) ].

7.3 Drugs that Prolong QT and Concomitant CYP3A4 Inhibitors

Recommend ECG in patients taking drugs with Sedoril-DCP (Dextromethorphan Hydrochloride) that prolong the QT interval and in patients taking concomitant moderate or strong CYP3A4 inhibitors [ see Warnings and Precautions ( 5.3 ) ].

7.4 SSRIs and Tricyclic Antidepressants

Use of Sedoril-DCP with SSRIs or tricyclic antidepressants increases the risk of ‘serotonin syndrome’ [ see Warnings and Precautions ( 5.6 ) ].

7.5 CYP2D6 Substrate

The co-administration of Sedoril-DCP (Dextromethorphan Hydrochloride) with drugs that undergo extensive CYP2D6 metabolism may result in altered drug effects, due to accumulation of parent drug and/or failure of metabolite formation [ see Warnings and Precautions ( 5.4 ) ] . Therapy with medications that are primarily metabolized by CYP2D6 and that have a relatively narrow therapeutic index should be initiated at a low dose if a patient is receiving Sedoril-DCP (Dextromethorphan Hydrochloride) concurrently. If Sedoril-DCP (Dextromethorphan Hydrochloride) is added to the treatment regimen of a patient already receiving a drug primarily metabolized by CYP2D6, the need for a dose modification of the original medication should be considered. The extent to which CYP2D6 interactions may pose clinical problems will depend on the pharmacokinetics of the substrate involved.

In cases of prodrugs whose actions are mediated by the CYP2D6-produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in the presence of Sedoril-DCP (Dextromethorphan Hydrochloride) due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with Sedoril-DCP (Dextromethorphan Hydrochloride) when clinically indicated.

Drug interactions with desipramine and paroxetine have been studied in controlled clinical trials with a higher dose combination of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) than Sedoril-DCP (Dextromethorphan Hydrochloride); study results are described below. No other drug interactions with CYP2D6 substrates have been systematically investigated, although concomitant use of such drugs was allowed in clinical trials with Sedoril-DCP (Dextromethorphan Hydrochloride) and in clinical trials with higher dose formulations of dextromethorphan/quinidine.

Desipramine (CYP2D6 substrate):

The tricyclic antidepressant desipramine is metabolized primarily by CYP2D6. A drug interaction study was conducted between a higher combination dose of Sedoril-DCP (Dextromethorphan Hydrochloride) (dextromethorphan 30 mg/quinidine 30 mg) and desipramine 25 mg. The combination dose of dextromethorphan/quinidine increased steady state desipramine levels approximately 8-fold. If Sedoril-DCP (Dextromethorphan Hydrochloride) and desipramine are prescribed concomitantly, the initial dose of desipramine should be markedly reduced. The dose of desipramine can then be adjusted based on clinical response; however, a dose above 40 mg/day is not recommended.

Paroxetine (CYP2D6 inhibitor and substrate) :

When the combination dose of dextromethorphan 30 mg/quinidine 30 mg was added to paroxetine at steady state, paroxetine exposure (AUC_0-24) increased by 1.7 fold and C_max increased by 1.5 fold. Consideration should be given to initiating treatment with a lower dose of paroxetine if given with Sedoril-DCP (Dextromethorphan Hydrochloride). The dose of paroxetine can then be adjusted based on clinical response; however, dosage above 35 mg/day is not recommended.

7.6 Digoxin

Quinidine is an inhibitor of P-glycoprotein. Concomitant administration of quinidine with digoxin, a P-glycoprotein substrate, results in serum digoxin levels that may be as much as doubled. Plasma digoxin concentrations should be closely monitored in patients taking Sedoril-DCP concomitantly, and the digoxin dose reduced, as necessary.

7.7 Alcohol

As with any other CNS drug, caution should be used when Sedoril-DCP (Dextromethorphan Hydrochloride) is taken in combination with other centrally acting drugs and alcohol.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Based on animal data, may cause fetal harm.
  

• Pediatric Use: Safety and effectiveness have not been established. (8.4)

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of Sedoril-DCP (Dextromethorphan Hydrochloride) in pregnant women. In oral studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including teratogenicity (rabbits) and embryolethality, when given to pregnant animals. Sedoril-DCP (Dextromethorphan Hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

When dextromethorphan/quinidine was administered orally (0/0, 5/100, 15/100, and 50/100 mg/kg/day) to pregnant rats during the period of organogenesis, embryo-fetal deaths were observed at the highest dose tested and reduced skeletal ossification was observed at all doses. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the recommended human dose (RHD) of 40/20 mg/day on a mg/m² basis. Oral administration (0/0, 5/60, 15/60, and 30/60 mg/kg/day) to pregnant rabbits during organogenesis resulted in an increased incidence of fetal malformations at all but the lowest dose tested. The no-effect dose (5/60 mg/kg/day) is approximately 2/60 times the RHD on a mg/m² basis.

When dextromethorphan/quinidine was orally administered (0/0, 5/100, 15/100, and 30/100 mg/kg/day) to female rats during pregnancy and lactation, pup survival and pup weight were decreased at all doses and developmental delay was seen in offspring at the mid- and high-doses. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the RHD on a mg/m² basis.

8.2 Labor and Delivery

The effects of Sedoril-DCP on labor and delivery are unknown.

8.3 Nursing Mothers

It is not known whether Sedoril-DCP (Dextromethorphan Hydrochloride) and/or quinidine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sedoril-DCP (Dextromethorphan Hydrochloride) is administered to a nursing mother.

8.4 Pediatric Use

The safety and effectiveness of Sedoril-DCP in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use

Of the total number of patients with PBA in clinical studies of Sedoril-DCP (Dextromethorphan Hydrochloride), 14 percent were 65 years old and over, while 2 percent were 75 and over. Clinical study of Sedoril-DCP (Dextromethorphan Hydrochloride) did not include sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients.

8.6 Renal Impairment

Dose adjustment of Sedoril-DCP is not required in patients with mild to moderate renal impairment [ see Clinical Pharmacology ( 12.3 )]. The pharmacokinetics of Sedoril-DCP (Dextromethorphan Hydrochloride) have not been evaluated in patients with severe renal impairment; however, increases in dextromethorphan and/or quinidine levels are likely to be observed.

8.7 Hepatic Impairment

Dose adjustment of Sedoril-DCP (Dextromethorphan Hydrochloride) is not required in patients with mild to moderate hepatic impairment. The pharmacokinetics of Sedoril-DCP (Dextromethorphan Hydrochloride) have not been evaluated in patients with severe hepatic impairment; however, increases in Sedoril-DCP (Dextromethorphan Hydrochloride) and/or quinidine levels are likely to be observed.

9 DRUG ABUSE AND DEPENDENCE

Sedoril-DCP (Dextromethorphan Hydrochloride) is a low-affinity uncompetitive NMDA antagonist and sigma-1 receptor agonist that has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, Sedoril-DCP (Dextromethorphan Hydrochloride) is a combination product containing Sedoril-DCP (Dextromethorphan Hydrochloride) and quinidine, and cases of Sedoril-DCP (Dextromethorphan Hydrochloride) abuse have been reported, predominantly in adolescents.

While clinical trials did not reveal drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this experience the extent to which Sedoril-DCP (Dextromethorphan Hydrochloride) will be misused, diverted, and/or abused once marketed. Therefore, patients with a history of drug abuse should be observed closely for signs of Sedoril-DCP (Dextromethorphan Hydrochloride) misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE

Evaluation and treatment of Sedoril-DCP overdose is based on experience with the individual components, Sedoril-DCP (Dextromethorphan Hydrochloride) and quinidine. Metabolism of the Sedoril-DCP (Dextromethorphan Hydrochloride) component of Sedoril-DCP (Dextromethorphan Hydrochloride) is inhibited by the quinidine component, such that adverse effects of overdose due to Sedoril-DCP (Dextromethorphan Hydrochloride) might be more severe or more persistent compared to overdose of Sedoril-DCP (Dextromethorphan Hydrochloride) alone.

During development of Sedoril-DCP (Dextromethorphan Hydrochloride), dose combinations of dextromethorphan/quinidine containing up to 6-times higher Sedoril-DCP (Dextromethorphan Hydrochloride) dose and 12-times higher quinidine dose were studied. The most common adverse events were mild to moderate nausea, dizziness, and headache.

The most important adverse effects of acute quinidine overdose are ventricular arrhythmias and hypotension. Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium.

While therapeutic doses of quinidine for treatment of cardiac arrhythmia or malaria are generally 10-fold, or more, higher than the dose of quinidine in Sedoril-DCP (Dextromethorphan Hydrochloride), potentially fatal cardiac arrhythmia, including torsades de pointes, can occur at quinidine exposures that are possible from Sedoril-DCP (Dextromethorphan Hydrochloride) overdose.

Adverse effects of Sedoril-DCP (Dextromethorphan Hydrochloride) overdose include nausea, vomiting, stupor, coma, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Sedoril-DCP (Dextromethorphan Hydrochloride) may cause serotonin syndrome, and this risk is increased by overdose, particularly if taken with other serotonergic agents, SSRIs or tricyclic antidepressants.

10.1 Treatment of Overdose

While serum quinidine levels can be measured, electrocardiographic monitoring of the QTc interval is a better predictor of quinidine-induced arrhythmia. Treatment of hemodynamically unstable polymorphic ventricular tachycardia (including torsades de pointes) is either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QTc interval. Factors contributing to QTc prolongation (especially hypokalemia and hypomagnesemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent torsades de pointes may require sustained overdrive pacing or the cautious administration of isoproterenol (30-150 ng/kg/min).

Because of the theoretical possibility of QT-prolonging effects that might be additive to those of quinidine, other antiarrhythmics with Class I (procainamide) or Class III activities should (if possible) be avoided.

If the post-cardioversion QTc interval is prolonged, then the pre-cardioversion polymorphic ventricular tachyarrhythmia was (by definition) torsades de pointes. In this case, class Ib antiarrhythmics like lidocaine are unlikely to be of value, and other Class I and Class III antiarrhythmics are likely to exacerbate the situation.

Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Treatment of hypotension should be directed at symptomatic and supportive measures. Repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine).

Quinidine:

Adequate studies of orally administered activated charcoal in human overdoses of quinidine have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of quinidine in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water. Although renal elimination of quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit. Quinidine is not usefully removed from the circulation by dialysis. Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

Sedoril-DCP (Dextromethorphan Hydrochloride):

Treatment of Sedoril-DCP (Dextromethorphan Hydrochloride) overdosage should be directed at symptomatic and supportive measures.

11 DESCRIPTION

Sedoril-DCP (Dextromethorphan Hydrochloride) is an oral formulation of Sedoril-DCP (Dextromethorphan Hydrochloride) hydrobromide USP and quinidine sulfate USP in a fixed dose combination.

Sedoril-DCP (Dextromethorphan Hydrochloride) hydrobromide is the pharmacologically active ingredient of Sedoril-DCP (Dextromethorphan Hydrochloride) that acts on the central nervous system (CNS). The chemical name is Sedoril-DCP (Dextromethorphan Hydrochloride) hydrobromide: morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C₁₈H₂₅NO-HBr-H₂O with a molecular weight of 370.33. The structural formula is:

Two additional studies conducted using a higher dose combination of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) provided supportive evidence of Sedoril-DCP (Dextromethorphan Hydrochloride) efficacy. The first was a 4 week study in PBA patients with underlying ALS, and the second was a 12 week study in patients with underlying MS. In both studies, the primary outcome measure, CNS-LS, and the secondary outcome measure, laughing and crying episodes, were statistically significantly decreased by the dextromethorphan/quinidine combination.

Figure 1: Mean PBA Episode Rates by Visit Figure 2: Least Square Mean CNS-LS Scores by Visit

16 HOW SUPPLIED/STORAGE AND HANDLING

Sedoril-DCP (Dextromethorphan Hydrochloride) is supplied as brick red gelatin capsules imprinted with “DMQ 20-10”. Sedoril-DCP (Dextromethorphan Hydrochloride) is supplied in the following package configuration:

Storage

Store Sedoril-DCP (Dextromethorphan Hydrochloride) capsules at controlled room temperature, 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) .

17 PATIENT COUNSELING INFORMATION

Hypersensitivity

Patients should be advised a hypersensitivity reaction to Sedoril-DCP (Dextromethorphan Hydrochloride) could occur. Patients should be instructed to seek medical attention immediately if they experience symptoms indicative of hypersensitivity after taking Sedoril-DCP (Dextromethorphan Hydrochloride) [ see Contraindications ( 4.2 ), Warnings and Precautions ( 5.1 ) ].

Cardiac effects

Patients should be advised to consult their healthcare provider immediately if they feel faint or lose consciousness. Patients should be counseled to inform their healthcare provider if they have any personal or family history of QTc prolongation [ see Contraindications ( 4.4 ), Warnings and Precautions ( 5.3 ) Drug Interactions ( 7 ) ].

Dizziness

Patients should be advised that Sedoril-DCP (Dextromethorphan Hydrochloride) may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls [ see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 ) ].

Drug Interactions

Inform patients that Sedoril-DCP (Dextromethorphan Hydrochloride) increases the risk of adverse drug interactions. Instruct patients to inform their healthcare provider about all the medications that they are taking before taking Sedoril-DCP (Dextromethorphan Hydrochloride). Before taking any new medications, patients should tell their healthcare provider that they are taking Sedoril-DCP (Dextromethorphan Hydrochloride) [ s ee Drug Interactions ( 7 ) ].

Dosing Instructions

Instruct patients to take Sedoril-DCP (Dextromethorphan Hydrochloride) exactly as prescribed. Instruct patients not to take more than 2 capsules in a 24-hour period and to make sure that there is an approximate 12-hour interval between doses, and not to take a double dose after they miss a dose [see Dosage and Administration ( 2.1 )].

General

Patients should not share or give Sedoril-DCP (Dextromethorphan Hydrochloride) to others, even if they have the same symptoms, because it may harm them.

Advise patients to contact their healthcare provider if their PBA symptoms persist or worsen.

Advise patients to keep this and all medications out of reach of children and pets.

Marketed by:

Avanir Pharmaceuticals, Inc.

Aliso Viejo, CA 92656

1-949-389-6700

Revised January 2016

Part No. 2000007715

AVANIR and Sedoril-DCP (Dextromethorphan Hydrochloride) are trademarks or registered trademarks of

Avanir Pharmaceuticals, Inc. in the United States and other countries.

U.S. Patent Nos.: 8,227,484 and 7,659,282

©2010-2016 Avanir Pharmaceuticals, Inc. All rights reserved.

Menthol:

• Sedoril-DCP (Menthol) reviews

Indication: Used to treat occasional minor irritation, pain, sore mouth, and sore throat as well as cough associated with a cold or inhaled irritants.

Sedoril-DCP (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. Menthol's ability to chemically trigger cold-sensitive receptors in the skin is responsible for the well known cooling sensation that it provokes when inhalated, eaten, or applied to the skin. It should be noted that Sedoril-DCP (Menthol) does not cause an actual drop in temperature.

Phenylpropanolamine Hydrochloride:

• Sedoril-DCP (Phenylpropanolamine Hydrochloride) reviews

Indication: For the treatment of nasal congestion, control of urinary incontinence, priapism and obesity.

Sedoril-DCP (Phenylpropanolamine Hydrochloride) (PPA), a sympathomimetic agent structurally similar to pseudoephedrine, is used to treat nasal congestion. Sedoril-DCP (Phenylpropanolamine Hydrochloride) is found in appetite suppressant formulations and with guaifenesinin in cough-cold formulations. In 2000, the FDA requested that all drug companies discontinue marketing products containing Sedoril-DCP (Phenylpropanolamine Hydrochloride), due to an increased risk of hemorrhagic stroke in women who used Sedoril-DCP (Phenylpropanolamine Hydrochloride).