Indikof-A

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Indikof-A uses

Indikof-A consists of Cetirizine, Dextromethorphan Hydrochloride, Menthol.

Cetirizine:



Drug Facts

Active ingredients

Indikof-A (Cetirizine) HCl 5 mg

Pseudoephedrine HCl 120 mg

Purpose

Antihistamine

Nasal decongestant

Uses

  • temporarily relieves these symptoms due to hay fever or other upper respiratory allergies:
    • runny nose
    • sneezing
    • itchy, watery eyes
    • itching of the nose or throat
    • nasal congestion
  • reduces swelling of nasal passages
  • temporarily relieves sinus congestion and pressure
  • temporarily restores freer breathing through the nose

Warnings

Do not use

  • if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine.
  • if you are 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 prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Ask a doctor before use if you have

  • heart disease
  • thyroid disease
  • diabetes
  • glaucoma
  • high blood pressure
  • trouble urinating due to an enlarged prostate gland
  • liver or kidney disease. Your doctor should determine if you need a different dose.

Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives.

When using this product

  • do not use more than directed
  • drowsiness may occur
  • avoid alcoholic drinks
  • alcohol, sedatives, and tranquilizers may increase drowsiness
  • be careful when driving a motor vehicle or operating machinery

Stop use and ask a doctor if

  • an allergic reaction to this product occurs. Seek medical help right away.
  • you get nervous, dizzy, or sleepless
  • symptoms do not improve within 7 days or are accompanied by fever

If pregnant or breast-feeding:

  • if breast-feeding: not recommended
  • if pregnant: ask a health professional before use.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)

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Directions

  • do not break or chew tablet; swallow tablet whole
adults and children 12 years and over take 1 tablet every 12 hours; do not take more than 2 tablets in 24 hours.
adults 65 years and over ask a doctor
children under 12 years of age ask a doctor
consumers with liver or kidney disease ask a doctor

Other information

  • store between 20° to 25°C (68° to 77°F)
  • do not use if individual blister unit is open or torn
  • see back panel for lot number and expiration date

Inactive ingredients

colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide

Questions?

call 1-800-343-7805

Dextromethorphan Hydrochloride:


1 INDICATIONS AND USAGE

Indikof-A (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.

Indikof-A (Dextromethorphan Hydrochloride) is a combination product containing Indikof-A (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 Indikof-A (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.

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3 DOSAGE FORMS AND STRENGTHS

Indikof-A (Dextromethorphan Hydrochloride) capsules contain 20 mg Indikof-A (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: Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride). (4.2)

  • Use with an MAOI or within 14 days of stopping an MAOI. Allow 14 days after stopping Indikof-A (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

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

4.2 Hypersensitivity

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

4.3 MAOIs

Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) before starting an MAOI [ see Drug Interactions ( 7.1 ) ].

4.4 Cardiovascular

Indikof-A (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 ) ].

Indikof-A (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 ) ].

Indikof-A (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.

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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: Indikof-A (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 Indikof-A (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, Indikof-A (Dextromethorphan Hydrochloride) should not be restarted in sensitized patients, because more rapid and more severe thrombocytopenia than the original episode can occur. Indikof-A (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

Indikof-A 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 Indikof-A (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 Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride), and should be monitored during treatment.

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

5.4 Concomitant use of CYP2D6 Substrates

The quinidine in Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) that are metabolized by CYP2D6 [ see Drug Interactions ( 7.5 ) ].

5.5 Dizziness

Indikof-A 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 Indikof-A (Dextromethorphan Hydrochloride), 10% of patients on Indikof-A (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), Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) is intended to inhibit CYP2D6 so that higher exposure to Indikof-A (Dextromethorphan Hydrochloride) can be achieved compared to when Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) is not expected to contribute to the effectiveness of Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride).

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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 Indikof-A (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 Indikof-A (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.

Indikof-A (Dextromethorphan Hydrochloride)

N=107

%

Placebo

N=109

%

Diarrhea 13 6
Dizziness 10 5
Cough 5 2
Vomiting 5 1
Asthenia 5 2
Peripheral edema 5 1
Urinary tract infection 4 1
Influenza 4 1
Increased gamma-

glutamyltransferase

3 0
Flatulence 3 1

6.2 Long-Term Exposure with Indikof-A

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 Indikof-A (Dextromethorphan Hydrochloride), Indikof-A (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.

Indikof-A (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 Indikof-A (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 Indikof-A (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 Indikof-A 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 Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) concurrently. If Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with Indikof-A (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 Indikof-A (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 Indikof-A (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 Indikof-A (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 Indikof-A (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 (AUC0-24) increased by 1.7 fold and Cmax increased by 1.5 fold. Consideration should be given to initiating treatment with a lower dose of paroxetine if given with Indikof-A (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 Indikof-A concomitantly, and the digoxin dose reduced, as necessary.

7.7 Alcohol

As with any other CNS drug, caution should be used when Indikof-A (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 Indikof-A (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. Indikof-A (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 Indikof-A on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

The safety and effectiveness of Indikof-A 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 Indikof-A (Dextromethorphan Hydrochloride), 14 percent were 65 years old and over, while 2 percent were 75 and over. Clinical study of Indikof-A (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 Indikof-A is not required in patients with mild to moderate renal impairment [ see Clinical Pharmacology ( 12.3 )]. The pharmacokinetics of Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) is not required in patients with mild to moderate hepatic impairment. The pharmacokinetics of Indikof-A (Dextromethorphan Hydrochloride) have not been evaluated in patients with severe hepatic impairment; however, increases in Indikof-A (Dextromethorphan Hydrochloride) and/or quinidine levels are likely to be observed.

9 DRUG ABUSE AND DEPENDENCE

Indikof-A (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, Indikof-A (Dextromethorphan Hydrochloride) is a combination product containing Indikof-A (Dextromethorphan Hydrochloride) and quinidine, and cases of Indikof-A (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 Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE

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

During development of Indikof-A (Dextromethorphan Hydrochloride), dose combinations of dextromethorphan/quinidine containing up to 6-times higher Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride), potentially fatal cardiac arrhythmia, including torsades de pointes, can occur at quinidine exposures that are possible from Indikof-A (Dextromethorphan Hydrochloride) overdose.

Adverse effects of Indikof-A (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. Indikof-A (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.

Indikof-A (Dextromethorphan Hydrochloride):

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

11 DESCRIPTION

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

Indikof-A (Dextromethorphan Hydrochloride) hydrobromide is the pharmacologically active ingredient of Indikof-A (Dextromethorphan Hydrochloride) that acts on the central nervous system (CNS). The chemical name is Indikof-A (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 Indikof-A (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

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

Package Configuration

Capsule Strength (mg) NDC Code
Bottles of 60 (30 day supply) dextromethorphan 20 mg/ quinidine 10 mg 64597-301-60

Storage

Store Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride) could occur. Patients should be instructed to seek medical attention immediately if they experience symptoms indicative of hypersensitivity after taking Indikof-A (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 Indikof-A (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 Indikof-A (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 Indikof-A (Dextromethorphan Hydrochloride). Before taking any new medications, patients should tell their healthcare provider that they are taking Indikof-A (Dextromethorphan Hydrochloride) [ s ee Drug Interactions ( 7 ) ].

Dosing Instructions

Instruct patients to take Indikof-A (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 Indikof-A (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 Indikof-A (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:


Indikof-A (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of Indikof-A (Menthol) occurring in nature is (-)-menthol, which is assigned the (1R,2S,5R) configuration. Indikof-A (Menthol) has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.

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

Indikof-A (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 Indikof-A (Menthol) does not cause an actual drop in temperature.

Indikof-A pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Indikof-A available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Indikof-A destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Indikof-A Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Indikof-A pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."MYOGESIC-CS (MENTHOL ) SPRAY [VETGENIX]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."KIRKLANDS CHILDRENS ALLER TEC (CETIRIZINE) LIQUID [COSTCO WHOLESALE COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."DEXTROMETHORPHAN HYDROBROMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Indikof-A?

Depending on the reaction of the Indikof-A after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Indikof-A not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Indikof-A addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Indikof-A, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Indikof-A consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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