Intervein may be available in the countries listed below.
Trimetazidine dihydrochloride (a derivative of Trimetazidine) is reported as an ingredient of Intervein in the following countries:
International Drug Name Search
MOR-feen SUL-fate, nal-TREX-one hye-droe-KLOR-ide
Morphine sulfate/naltrexone hydrochloride capsules contain pellets of morphine sulfate with a sequestered core of naltrexone, and is indicated for moderate to severe pain management. Drug should be swallowed whole or the capsule contents sprinkled on apple sauce. Pellets are not to be chewed, crushed, or dissolved. Misuse causes rapid release and absorption, with a resulting potentially-fatal morphine dose. Capsules are for use in opioid-tolerant patients only and are not intended for prn analgesia. Patients should not consume alcoholic beverages or medications containing alcohol while on this drug .
In the U.S.
Available Dosage Forms:
Pharmacologic Class: Naltrexone
Chemical Class: Morphine
Morphine and naltrexone combination is used to treat moderate to severe pain when around-the-clock pain relief is needed for a long period of time. morphine and naltrexone should not be used to treat pain that you only have once in a while (or "as needed").
Morphine belongs to the group of medicines called narcotic analgesics (pain medicines). It acts on the central nervous system (CNS) to relieve pain.
Naltrexone is an opioid antagonist. It blocks the effects of narcotics, especially the "high'' feeling that makes you want to use them. It will not produce any narcotic-like effects or cause mental or physical dependence.
morphine and naltrexone is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For morphine and naltrexone, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to morphine and naltrexone or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of morphine and naltrexone combination in the pediatric population. Safety and efficacy have not been established.
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of morphine and naltrexone combination in the elderly. However, elderly patients are more likely to have age-related heart, kidney, liver, or lung problems, which may require an adjustment in the dose for patients receiving morphine and naltrexone combination.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking morphine and naltrexone, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using morphine and naltrexone with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using morphine and naltrexone with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using morphine and naltrexone with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using morphine and naltrexone with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use morphine and naltrexone, or give you special instructions about the use of food, alcohol, or tobacco.
The presence of other medical problems may affect the use of morphine and naltrexone. Make sure you tell your doctor if you have any other medical problems, especially:
Morphine and naltrexone combination extended-release capsules are for use in opioid-tolerant patients only. If you are uncertain whether or not you are opioid-tolerant, check with your doctor before using morphine and naltrexone.
morphine and naltrexone should come with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.
Swallow the extended-release capsules whole. Do not break, crush, or chew it.
If you cannot swallow the extended-release capsule, you may open it and pour the medicine into a small amount of soft food such as applesauce. Stir this mixture well and swallow it without chewing.
The dose of morphine and naltrexone will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of morphine and naltrexone. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of morphine and naltrexone, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Flush the unused Embeda® capsules down the toilet.
It is very important that your doctor check your progress while you are taking morphine and naltrexone. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.
morphine and naltrexone will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the other medicines listed above while you are using morphine and naltrexone.
morphine and naltrexone may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.
Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve dizziness or lightheadedness.
Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.
Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are using morphine and naltrexone. Serious side effects can occur if your medical doctor or dentist gives you certain other medicines without knowing that you are using morphine and naltrexone combination.
morphine and naltrexone may make you dizzy, drowsy, or lightheaded. Make sure you know how you react to morphine and naltrexone before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.
morphine and naltrexone may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using morphine and naltrexone.
If you have been using morphine and naltrexone regularly for several weeks or more, do not suddenly stop using it without first checking with your doctor. You may be directed to gradually reduce the amount you are using before stopping treatment completely, or to take another narcotic for a while, to lessen the chance of withdrawal side effects.
Using morphine and naltrexone while you are pregnant may cause neonatal withdrawal syndrome in your newborn babies. Tell your doctor right away if you child has the following symptoms: abnormal sleep pattern, diarrhea, high-pitched cry, irritability, shakiness or tremor, weight loss, vomiting, or failure to gain weight.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: morphine and naltrexone side effects (in more detail)
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Tessalon, a non-narcotic oral antitussive agent, is 2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl p-(butylamino) benzoate; with a molecular weight of 603.7.
Each Tessalon Capsule contains:
Tessalon Capsules also contain: D&C Yellow 10, gelatin, glycerin, methylparaben and propylparaben.
Tessalon acts peripherally by anesthetizing the stretch receptors located in the respiratory passages, lungs, and pleura by dampening their activity and thereby reducing the cough reflex at its source. It begins to act within 15 to 20 minutes and its effect lasts for 3 to 8 hours. Tessalon has no inhibitory effect on the respiratory center in recommended dosage.
Tessalon is indicated for the symptomatic relief of cough.
Hypersensitivity to benzonatate or related compounds.
Severe hypersensitivity reactions (including bronchospasm, laryngospasm and cardiovascular collapse) have been reported which are possibly related to local anesthesia from sucking or chewing the capsule instead of swallowing it. Severe reactions have required intervention with vasopressor agents and supportive measures.
Isolated instances of bizarre behavior, including mental confusion and visual hallucinations, have also been reported in patients taking Tessalon in combination with other prescribed drugs.
Keep Tessalon out of reach of children. Accidental ingestion of Tessalon resulting in death has been reported in children below age 10. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. If accidental ingestion occurs, seek medical attention immediately (see OVERDOSAGE).
Benzonatate is chemically related to anesthetic agents of the para-amino-benzoic acid class (e.g. procaine; tetracaine) and has been associated with adverse CNS effects possibly related to a prior sensitivity to related agents or interaction with concomitant medication.
Swallow Tessalon Capsules and Perles whole. Do not break, chew, dissolve, cut, or crush Tessalon Capsules and Perles. Release of Tessalon from the capsule in the mouth can produce a temporary local anesthesia of the oral mucosa and choking could occur. If numbness or tingling of the tongue, mouth, throat, or face occurs, refrain from oral ingestion of food or liquids until the numbness has resolved. If the symptoms worsen or persist, seek medical attention.
Keep Tessalon out of reach of children. Accidental ingestion resulting in death has been reported in children. Signs and symptoms of overdose have been reported within 15-20 minutes and death has been reported within one hour of ingestion. Signs and symptoms may include restlessness, tremors, convulsions, coma and cardiac arrest. If accidental ingestion occurs, seek medical attention immediately.
Overdosage resulting in death may occur in adults.
Do not exceed a single dose of 200 mg and a total daily dosage of 600 mg. If you miss a dose of Tessalon, skip that dose and take the next dose at the next scheduled time. Do not take 2 doses of Tessalon at one time.
Animal reproduction studies have not been conducted with Tessalon. It is also not known whether Tessalon can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tessalon should be given to a pregnant woman only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when Tessalon is administered to a nursing woman.
Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Tessalon.
Safety and effectiveness in children below the age of 10 have not been established. Accidental ingestion resulting in death has been reported in children below age 10. Keep out of reach of children.
Potential Adverse Reactions to Tessalon may include:
Hypersensitivity reactions including bronchospasm, laryngospasm, cardiovascular collapse possibly related to local anesthesia from chewing or sucking the capsule.
sedation; headache; dizziness; mental confusion; visual hallucinations.
constipation; nausea; GI upset.
nasal congestion; sensation of burning in the eyes; vague “chilly” sensation; numbness of the chest; hypersensitivity.
Deliberate or accidental overdose has resulted in death, particularly in children.
Intentional and unintentional overdose may result in death, particularly in children.
The drug is chemically related to tetracaine and other topical anesthetics and shares various aspects of their pharmacology and toxicology. Drugs of this type are generally well absorbed after ingestion.
The signs and symptoms of overdose of benzonatate have been reported within 15-20 minutes. If capsules are chewed or dissolved in the mouth, oropharyngeal anesthesia will develop rapidly, which may cause choking and airway compromise.
CNS stimulation may cause restlessness and tremors which may proceed to clonic convulsions followed by profound CNS depression. Convulsions, coma, cerebral edema and cardiac arrest leading to death have been reported within 1 hour of ingestion.
In case of overdose, seek medical attention immediately. Evacuate gastric contents and administer copious amounts of activated charcoal slurry. Even in the conscious patient, cough and gag reflexes may be so depressed as to necessitate special attention to protection against aspiration of gastric contents and orally administered materials. Convulsions should be treated with a short-acting barbiturate given intravenously and carefully titrated for the smallest effective dosage. Intensive support of respiration and cardiovascular-renal function is an essential feature of the treatment of severe intoxication from overdosage.
Adults and Children over 10 years of age: Usual dose is one 100 mg or 200 mg capsule three times a day as needed for cough. If necessary to control cough, up to 600 mg daily in three divided doses may be given. Tessalon should be swallowed whole. Tessalon Capsules and Perles are not to be broken, chewed, dissolved, cut or crushed.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Tessalon 100 mg/200 mg (benzonatate, USP) perles/capsules
See package insert for dosage information
Dispensing package for professional use only.
Dispense in a tight, light-resistant container as defined in the USP.
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA011210 | 02/10/1958 | |
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| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA011210 | 06/25/1999 | |
| Labeler - Pfizer Laboratories (134489525) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Catalent Pharma Solutions, LLC | 051762268 | MANUFACTURE | |
Generic Name: acetaminophen, chlorpheniramine, and phenylephrine (a SEET a MIN oh fen, KLOR fen EER a meen, FEN ill EFF rin)
Brand Names: Alka-Seltzer Plus Cold, Allergy Relief Multi-Symptom, Comtrex Flu Therapy, Comtrex Severe Cold & Sinus, Contac Cold+Flu, Dristan Cold Multi Symptom Formula, Protid, Robitussin Nighttime Nasal Relief, Sinus Congestion & Pain Nighttime, Tylenol Allergy Multi-Symptom, Tylenol Children's Plus Cold, Tylenol Sinus Congestion and Pain Cool Burst Day Night, Tylenol Sinus Congestion Nighttime
Acetaminophen is a pain reliever and fever reducer.
Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.
Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).
The combination of acetaminophen, chlorpheniramine, and phenylephrine is used to treat headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.
Acetaminophen, chlorpheniramine, and phenylephrine may also be used for purposes not listed in this medication guide.
Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:
liver disease, cirrhosis, or a history of alcoholism;
a blockage in your digestive tract (stomach or intestines);
diabetes;
kidney disease;
epilepsy or other seizure disorder;
cough with mucus, or cough caused by smoking, emphysema, or chronic bronchitis;
enlarged prostate or urination problems;
low blood pressure;
pheochromocytoma (an adrenal gland tumor); or
if you take potassium (Cytra, Epiklor, K-Lyte, K-Phos, Kaon, Klor-Con, Polycitra, Urocit-K).
Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. This medicine is usually taken only for a short time until your symptoms clear up.
Measure liquid medicine with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Drop the effervescent tablets into a glass of water (at least 4 ounces, or one-half cup). Stir this mixture and drink all of it right away.
Do not take for longer than 7 days in a row. Stop taking the medicine and call your doctor if you still have a fever after 3 days of use, you still have pain after 7 days (or 5 days if treating a child), if your symptoms get worse, or if you have a skin rash, ongoing headache, or any redness or swelling.
Since this medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.
Overdose symptoms may also include severe forms of some of the side effects listed in this medication guide.
chest pain, rapid pulse, fast or uneven heart rate;
confusion, hallucinations, severe nervousness;
tremor, seizure (convulsions);
easy bruising or bleeding, unusual weakness;
urinating less than usual or not at all;
nausea, pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of your skin or eyes); or
dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats, seizure).
Less serious side effects may include:
dizziness, drowsiness;
mild headache;
dry mouth, nose, or throat;
constipation;
blurred vision;
feeling nervous; or
sleep problems (insomnia);
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Tell your doctor about all other medicines you use, especially:
leflunomide (Arava);
topiramate (Topamax);
zonisamide (Zonegran);
an antibiotic, antifungal medicine, sulfa drug, or tuberculosis medicine;
an antidepressant;
birth control pills or hormone replacement therapy;
bladder or urinary medications;
blood pressure medication;
a bronchodilator;
cancer medicine;
cholesterol-lowering medications such as Lipitor, Niaspan, Zocor, Vytorin, and others;
gout or arthritis medications (including gold injections);
HIV/AIDS medication;
medication for nausea and vomiting, stomach ulcers, or irritable bowel syndrome;
medicines to treat psychiatric disorders;
an NSAID such as Advil, Aleve, Arthrotec, Cataflam, Celebrex, Indocin, Motrin, Naprosyn, Treximet, Voltaren, others; or
seizure medication.
This list is not complete and other drugs may interact with acetaminophen, chlorpheniramine, and phenylephrine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.
See also: Alka-Seltzer Plus Cold side effects (in more detail)
Generic Name: methyltestosterone (METH il tes TOS te role)
Brand Names: Android, Methitest, Testred
Methyltestosterone is a man-made form of testosterone, a naturally occurring sex hormone that is produced in a man's testicles. Small amounts of testosterone are also produced in a woman's ovaries and adrenal system.
Methyltestosterone is used in men and boys to treat conditions caused by a lack of this hormone, such as delayed puberty or other hormonal imbalances. Methyltestosterone is also used in women to treat breast cancer that has spread to other parts of the body.
Methyltestosterone may also be used for other purposes not listed in this medication guide.
Before receiving methyltestosterone, tell your doctor if you have benign prostatic hypertrophy, breast cancer, a bleeding or blood clotting disorder, liver or kidney disease, heart disease, coronary artery disease, congestive heart failure, or a history of heart attack.
To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.
prostate cancer;
male breast cancer; or
if you are pregnant.
Before receiving methyltestosterone, tell your doctor if you are allergic to any drugs, or if you have:
benign prostatic hypertrophy (BPH);
breast cancer;
a bleeding or blood clotting disorder;
delayed puberty;
liver or kidney disease; or
heart disease, coronary artery disease (hardened arteries), congestive heart failure, or a history of heart attack.
If you have any of these conditions, you may need a dose adjustment or special tests to safely take methyltestosterone.
Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.
Your doctor may occasionally change your dose to make sure you get the best results from this medication.
To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.
Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.
An overdose of methyltestosterone is not expected to cause life-threatening symptoms.
Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using methyltestosterone.
feeling short of breath, even with mild exertion;
swelling, rapid weight gain;
increased or ongoing erection of the penis;
bone pain, increased thirst, memory problems, restless feeling, confusion, nausea, loss of appetite, increased urination, weakness, muscle twitching; or
nausea, vomiting, stomach pain, loss of appetite, and jaundice (yellowing of the skin or eyes).
changes in menstrual periods;
male-pattern hair growth (such as on the chin or chest);
hoarse voice; or
Less serious side effects (in men or women) may include:
acne, changes in skin color;
breast swelling;
male pattern baldness;
headache, anxiety, depressed mood;
mild nausea;
numbness or tingly feeling; or
increased or decreased interest in sex.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.
The following drugs can interact with methyltestosterone. Tell your doctor if you are using any of these:
a blood thinner such as warfarin (Coumadin); or
insulin or diabetes medication you take by mouth.
This list is not complete and there may be other drugs that can affect methyltestosterone. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
See also: Android side effects (in more detail)
Nuedexta is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurological 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.
Studies to support the effectiveness of Nuedexta were performed in patients with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Nuedexta has not been shown to be safe and effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.
The recommended starting dose of Nuedexta 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.
Nuedexta capsules contain 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate in a brick red gelatin capsule with “DMQ / 20-10” printed in white ink on the capsule.
Nuedexta contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine.
Nuedexta is contraindicated in patients with a history of Nuedexta, quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome. Nuedexta is also contraindicated in patients with a known hypersensitivity to dextromethorphan (e.g. rash, hives) [see Warnings and Precautions (5.1)].
Nuedexta 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 Nuedexta before starting an MAOI [see Drug Interactions (7.1)].
Nuedexta 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)].
Nuedexta 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)].
Nuedexta is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block.
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, Nuedexta should not be restarted in sensitized patients, because more rapid and more severe thrombocytopenia than the original episode can occur. Nuedexta 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.
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.
Nuedexta 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 Nuedexta 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 Nuedexta. 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 Nuedexta, and should be monitored during treatment.
If patients taking Nuedexta experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., syncope or palpitations, Nuedexta should be discontinued and the patient further evaluated.
The quinidine in Nuedexta inhibits CYP2D6 in patients in whom CYP2D6 is not otherwise genetically absent or its activity otherwise pharmacologically inhibited [see CYP2D6 Poor Metabolizers (5.8), Pharmacokinetics (12.3), Pharmacogenomics (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 Nuedexta that are metabolized by CYP2D6 [see Drug Interactions (7.5)].
Nuedexta 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 Nuedexta, 10% of patients on Nuedexta and 5% on placebo experienced dizziness.
When used with SSRIs (such as fluoxetine) or tricyclic antidepressants (such as clomipramine and imipramine), Nuedexta 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)].
Monitor for worsening clinical condition in myasthenia gravis and other conditions that may be adversely affected by anticholinergic effects.
The quinidine component of Nuedexta is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone [see Concomitant use of CYP2D6 substrates (5.4), Pharmacokinetics (12.3), Pharmacogenomics (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 Nuedexta is not expected to contribute to the effectiveness of Nuedexta 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 Nuedexta.
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 hydrobromide/quinidine sulfate 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 (45 patients) and traumatic brain injury (23 patients). Consequently, patients with other underlying neurologic diseases may experience other adverse reactions not described below.
A 12-week, placebo-controlled study evaluated Nuedexta (dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg) (N=107) and dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg combination (N=110) compared to placebo (N=109). Approximately 60% of patients had ALS and 40% 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.
The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) that led to discontinuation with the dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg twice daily dose were muscle spasticity (3%), respiratory failure (1%), abdominal pain (2%), asthenia (2%), dizziness (2%), fall (1%), and muscle spasms (2%).
Adverse drug reactions that occurred in ≥ 3% of patients receiving the dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg 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.
| Nuedexta 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 |
The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials.
The following adverse reactions have been reported with the use of the individual components of Nuedexta, dextromethorphan 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.
Dextromethorphan
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.
Do not use Nuedexta with monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days. [see Contraindications (4.3)].
Do not use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide) [see Contraindications (4.4)].
Recommend ECG in patients taking drugs with Nuedexta that prolong the QT interval and in patients taking concomitant moderate or strong CYP3A4 inhibitors [see Warnings and Precautions (5.3)].
Use of Nuedexta with SSRIs or tricyclic antidepressants increases the risk of ‘serotonin syndrome’ [see Warnings and Precautions (5.6)].
The co-administration of Nuedexta 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 Nuedexta concurrently. If Nuedexta 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 Nuedexta due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with Nuedexta 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 hydrobromide 30 mg/ quinidine sulfate 30 mg) than Nuedexta; 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 Nuedexta 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 dextromethorphan (dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg) and desipramine 25 mg. The combination dose of dextromethorphan/quinidine increased steady state desipramine levels approximately 8-fold. If Nuedexta 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 hydrobromide 30 mg/quinidine sulfate 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 Nuedexta. The dose of paroxetine can then be adjusted based on clinical response; however dosage above 35 mg/day is not recommended.
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 Nuedexta concomitantly, and the digoxin dose reduced, as necessary.
As with any other CNS drug, caution should be used when Nuedexta is taken in combination with other centrally acting drugs and alcohol.
Pregnancy Category C: There are no adequate and well-controlled studies of Nuedexta 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. Nuedexta 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.
The effects of Nuedexta on labor and delivery are unknown.
It is not known whether dextromethorphan and/or quinidine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nuedexta is administered to a nursing mother.
The safety and effectiveness of Nuedexta in pediatric patients below the age of 18 have not been established.
Of the total number of patients with PBA in clinical studies of Nuedexta, 14 percent were 65 years old and over, while 2 percent were 75 and over. Clinical study of Nuedexta did not include sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients.
Dose adjustment of Nuedexta is not required in patients with mild to moderate renal impairment [see Clinical Pharmacology (12.3)]. The pharmacokinetics of Nuedexta have not been evaluated in patients with severe renal impairment; however, increases in dextromethorphan and/or quinidine levels are likely to be observed.
Dose adjustment of Nuedexta is not required in patients with mild to moderate hepatic impairment. The pharmacokinetics of Nuedexta have not been evaluated in patients with severe hepatic impairment; however, increases in dextromethorphan and/or quinidine levels are likely to be observed.
Nuedexta 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, Nuedexta is a combination product containing dextromethorphan hydrobromide and quinidine sulfate, and cases of dextromethorphan abuse have been reported, predominately 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 Nuedexta will be misused, diverted, and/or abused once marketed. Therefore, patients with a history of drug abuse should be observed closely for signs of Nuedexta misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behavior).
Evaluation and treatment of Nuedexta overdose is based on experience with the individual components, dextromethorphan and quinidine. Metabolism of the dextromethorphan component of Nuedexta is inhibited by the quinidine component, such that adverse effects of overdose due to Nuedexta might be more severe or more persistent compared to overdose of dextromethorphan alone.
During development of Nuedexta, dose combinations of dextromethorphan/quinidine containing up to 6-times higher dextromethorphan 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 Nuedexta, potentially fatal cardiac arrhythmia, including torsades de pointes, can occur at quinidine exposures that are possible from Nuedexta overdose.
Adverse effects of dextromethorphan 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. Dextromethorphan may cause serotonin syndrome, and this risk is increased by overdose, particularly if taken with other serotonergic agents, SSRI’s or tricyclic antidepressants.
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.
Dextromethorphan: Treatment of dextromethorphan overdosage should be directed at symptomatic and supportive measures.
Nuedexta is an oral formulation of dextromethorphan hydrobromide USP and quinidine sulfate USP in a fixed dose combination.
Dextromethorphan hydrobromide is the pharmacologically active ingredient of Nuedexta that acts on the central nervous system (CNS). The chemical name is dextromethorphan 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:
Quinidine sulfate is a specific inhibitor of CYP2D6-dependent oxidative metabolism used in Nuedexta to increase the systemic bioavailability of dextromethorphan. The chemical name is quinidine sulfate: cinchonan-9-ol, 6’-methoxy- (9S) sulfate (2:1), (salt), dihydrate. Quinidine sulfate dihydrate has the empirical formula of (C20H24N2O2)2•H2SO4•2H2O with a molecular weight of 782.96. The structural formula is:
The combination product, Nuedexta, is a white to off-white powder. Nuedexta is available for oral use as Nuedexta which contains 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate. The active ingredients are dextromethorphan hydrobromide monohydrate USP and quinidine sulfate dihydrate USP.Inactive ingredients in the capsule are croscarmellose sodium NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, lactose monohydrate NF, and magnesium stearate NF.
Dextromethorphan (DM) is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown.
The effect of dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg (for 7 doses) on QTc prolongation was evaluate in a randomized, double-blind (except for moxifloxacin), placebo- and positive-controlled (400 mg moxifloxacin) crossover thorough QT study in 50 fasted normal healthy men and women with CYP2D6 extensive metabolizer (EM) genotype. Mean changes in QTcF were 6.8 ms for dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg and 9.1 ms for the reference positive control (moxifloxacin). The maximum mean (95% upper confidence bound) difference from placebo after baseline correction was 10.2 (12.6) ms. This test dose is adequate to represent the steady state exposure in patients with CYP2D6 extensive metabolizer phenotype.
The effects of supratherapeutic doses of dextromethorphan hydrobromide/quinidine sulfate (30 mg/30mg and 60mg/60mg, for 7 doses) on QTc prolongation was evaluated in a randomized, placebo-controlled, double-blind, crossover design with an additional open-label positive control (400-mg moxifloxacin) arm in 36 healthy volunteers. The maximum mean (95% upper confidence bound) differences from placebo after baseline-correction were 10.2 (14.6) and 18.4 (22.7) ms following dextromethorphan hydrobromide/quinidine sulfate doses of 30 mg/30 mg and 60/60 mg, respectively. The supratherapeutic doses are adequate to represent exposure increases due to drug-drug interactions and organ dysfunctions.
Nuedexta contains dextromethorphan and quinidine, both of which are metabolized primarily by liver enzymes. Quinidine’s primary pharmacological action in Nuedexta is to competitively inhibit the metabolism of dextromethorphan catalyzed by CYP2D6 in order to increase and prolong plasma concentrations of dextromethorphan [see Concomitant use of CYP2D6 substrates (5.4), CYP2D6 Poor Metabolizers (5.8), Pharmacogenomics (12.5)]. Studies were conducted with the individual components of Nuedexta in healthy subjects to determine single-dose and multiple-dose kinetics of orally administered dextromethorphan hydrobromide in combination with quinidine sulfate. The increase in dextromethorphan levels appeared approximately dose proportional when the dextromethorphan hydrobromide dose increased from 20 mg to 30 mg in the presence of 10 mg of quinidine sulfate.
Absorption: Following single and repeated combination doses of dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg, dextromethorphan hydrobromide/quinidine sulfate-treated subjects had an approximately 20-fold increase in dextromethorphan exposure compared to dextromethorphan given without quinidine.
Following repeated doses of dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg and dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg (Nuedexta), maximal plasma concentrations (Cmax) of dextromethorphan are reached approximately 3 to 4 hours after dosing and maximal plasma concentrations of quinidine are reached approximately 1 to 2 hours after dosing.
In extensive metabolizers, mean Cmax and AUC0-12 values of dextromethorphan and dextrorphan increased as doses of dextromethorphan increased from 20 to 30 mg and mean Cmax and AUC0-12 values of quinidine appeared similar.
The mean plasma Cmax of quinidine following twice daily co-administration of dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg in patients with PBA was within 1 to 3% of the concentrations required for antiarrhythmic efficacy (2 to 5 mcg/mL).
Nuedexta may be taken without regard to meals as food does not affect the exposure of dextromethorphan and quinidine significantly.
Distribution: After Nuedexta administration, protein binding remains essentially the same as that after administration of the individual components; dextromethorphan is approximately 60-70% protein bound and quinidine is approximately 80-89% protein bound.
Metabolism and Excretion: Nuedexta is a combination product containing dextromethorphan hydrobromide and quinidine sulfate. Dextromethorphan is metabolized by CYP2D6 and quinidine is metabolized by CYP3A4. After dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg administration in extensive metabolizers, the elimination half-life of dextromethorphan was approximately 13 hours and the elimination half-life of quinidine was approximately 7 hours.
There are several hydroxylated metabolites of quinidine. The major metabolite of quinidine is 3-hydroxyquinidine. The 3-hydroxymetabolite is considered to be at least half as pharmacologically active as quinidine with respect to cardiac effects such as QT prolongation.
When the urine pH is less than 7, about 20% of administered quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH-dependent) tubular reabsorption.
The pharmacokinetics of dextromethorphan/quinidine have not been investigated systematically in elderly subjects (aged > 65 years) although such subjects were included in the clinical program. A population pharmacokinetic analysis of 170 subjects (148 subjects < 65 years old and 22 subjects ≥ 65 years old) administered dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg revealed similar pharmacokinetics in subjects < 65 years and those ≥ 65 years of age.
The pharmacokinetics of Nuedexta in pediatric patients have not been studied.
A population pharmacokinetic analysis based on data from 109 subjects (75 male; 34 female) showed no apparent gender differences in the pharmacokinetics of Nuedexta.
A population pharmacokinetic analysis of race with 109 subjects (21 Caucasian; 71 Hispanic; 18 Black) revealed no apparent racial differences in the pharmacokinetics of Nuedexta.
In a study of a combination dose of dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg TWICE DAILY in 12 subjects with mild (CLCR 50-80 mL/min) or moderate (CLCR 30-50 mL/min) renal impairment (6 each) compared to 9 healthy subjects (matched in gender, age, and weight range to impaired subjects), subjects showed little difference in quinidine or dextromethorphan pharmacokinetics compared to healthy subjects. Dose adjustment is therefore not required in mild or moderate renal impairment. Nuedexta has not been studied in patients with severe renal impairment.
In a study of a combination dose of dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg TWICE DAILY in 12 subjects with mild or moderate hepatic impairment (as indicated by the Child-Pugh method; 6 each) compared to 9 healthy subjects (matched in gender, age, and weight range to impaired subjects), subjects with moderate hepatic impairment showed similar dextromethorphan AUC and Cmax and clearance compared to healthy subjects. Mild to moderate hepatic impairment had little effect on quinidine pharmacokinetics. Patients with moderate impairment showed an increased frequency of adverse events. Therefore, dosage adjustment is not required in patients with mild and moderate hepatic impairment, although additional monitoring for adverse reactions should be considered. Quinidine clearance is unaffected by hepatic cirrhosis, although there is an increased volume of distribution that leads to an increase in the elimination half-life. Neither dextromethorphan alone nor Nuedexta have been evaluated in patients with severe hepatic impairment.
The potential for dextromethorphan and quinidine to inhibit or induce cytochrome P450 in vitro were evaluated in human microsomes. Dextromethorphan did not inhibit (< 20% inhibition) any of the tested isoenzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in human liver microsomes at concentrations up to 5 microM. Quinidine did not inhibit (< 30% inhibition) CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4 in human microsomes at concentrations up to 5 microM. Quinidine inhibited CYP2D6 with a half maximal inhibitory concentration (IC50) of less than 0.05 microM. Neither dextromethorphan nor quinidine induced CYP1A2, CYP2B6 or CYP3A4 in human hepatocytes at concentrations up to 4.8 microM.
Desipramine (CYP2D6 substrate): Co-administration of dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg with the tricyclic antidepressant desipramine, a CYP2D6 substrate, when desipramine was given at a dose of 25 mg once daily in 13 healthy volunteers resulted in an approximately 8-fold increase in steady state desipramine exposure (Cmin) compared to desipramine given alone. Therefore, concomitant administration of Nuedexta and drugs undergoing CYP2D6 metabolism should be evaluated for appropriate dose adjustment or alternative medication if the concomitant medication depends primarily on CYP2D6 metabolism and has a narrow therapeutic index, or if it relies on CYP2D6 for conversion to an active species [see CYP2D6 Substrate (5.4)].
Paroxetine (CYP2D6 inhibitor and substrate): Co-administration of the selective serotonin reuptake inhibitor paroxetine and a higher combination dose of dextromethorphan/quinidine (dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg) was studied in 27 healthy volunteers. Group 1 (N=14) received paroxetine 20 mg once daily for 12 days followed by the addition of dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg twice daily for 8 days. Group 2 (N=13) received dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg twice daily for 8 days followed by the addition of paroxetine 20 mg once daily for 12 days. Dextromethorphan exposure (AUC0-12) and Cmax increased by 1.5 fold and 1.4 fold, respectively, and quinidine exposure (AUC0-12) and Cmax increased by 1.4 fold and 1.3 fold, respectively, and dextrorphan exposure (AUC0-12) and Cmax decreased by 14% and 18%, respectively, and paroxetine exposure (AUC0-24) and Cmax increased by 2.3 fold and 2.0 fold, respectively, when paroxetine was added to the combination dose of dextromethorphan/quinidine at steady state (Group 2).
When the combination dose of dextromethorphan/quinidine was added to paroxetine at steady state (Group 1), paroxetine exposure (AUC0-24) and Cmax increased by 1.7 fold and 1.5 fold, respectively, while dextromethorphan and quinidine exposure do not change significantly and dextrorphan exposure (AUC0-12) and Cmax decreased by 34% and 33%, respectively.
Based on these results, whenever Nuedexta is prescribed with drugs like paroxetine that inhibit or are extensively metabolized by CYP2D6, consideration should be given to initiating treatment with a lower dose. The dose of paroxetine can then be adjusted based on clinical response; however, dosage above 35 mg/day is not recommended [see CYP2D6 Substrate (5.4) ].
NMDA receptor antagonists (memantine): A drug interaction study was conducted between a higher combination dose of dextromethorphan/quinidine (dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg) and memantine 20 mg/day to investigate the pharmacokinetic and pharmacodynamic interactions in 52 healthy subjects. Both dextromethorphan and memantine are antagonists of the N-methyl-D-aspartate (NMDA) receptor which could theoretically result in an additive effect at NMDA receptors and potentially an increased incidence of adverse events. There was no significant difference in the plasma concentrations of dextromethorphan and dextrorphan before and after the administration of memantine. Plasma concentrations of quinidine increased 20-30% when memantine was added to dextromethorphan hydrobromide 30mg/quinidine sulfate 30mg.
The quinidine component of Nuedexta is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone. Approximately 7-10% of Caucasians and 3-8% of African Americans generally lack the capacity to metabolize CYP2D6 substrates and are classified as PMs. The quinidine component of Nuedexta is not expected to contribute to the effectiveness of Nuedexta 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 Nuedexta [see Concomitant Use of CYP2D6 Substrate (5.4), CYP2D6 Poor Metabolizer (5.8), Pharmacokinetics (12.3)].
Carcinogenesis
In a 26-week carcinogenicity study in the Tg.rasH2 transgenic mouse, dextromethorphan and quinidine, alone and in combination, at oral doses up to 100/100 mg/kg/day did not show any evidence of carcinogenic potential.
In a two-year carcinogenicity study in rats, dextromethorphan/quinidine were administered at oral doses of 0/0, 5/100, 20/100, 50/100, 50/0, 0/100 mg/kg/day. No biologically significant tumor findings were observed. The highest dose tested (50/100 mg/kg/day) is approximately 12/50 times the recommended human dose (RHD) of 40/20 mg/day on a mg/m2 basis.
Mutagenesis
Dextromethorphan/quinidine was negative in an in vitro chromosomal aberration assay in human lymphocytes.
Dextromethorphan was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (mouse micronucleus) assays.
Quinidine was negative in an in vitro bacterial reverse mutation assay and in an in vivo mouse micronucleus assay. Quinidine induced chromosomal aberrations in an in vitro chromosomal aberration assay in the presence of metabolic activation.
Impairment of Fertility
When dextromethorphan / quinidine was administered orally (0/0, 5/100, 15/100, and 50/100 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested, which is approximately 12/50 times the RHD on a mg/m2 basis.
The efficacy of Nuedexta was demonstrated in one trial in PBA patients with underlying amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Other trials at higher doses (dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg) provided supportive evidence.
In the Nuedexta trial, patients with PBA were randomized to receive Nuedexta dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg, (N=107), dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg (N=110), or placebo (N=109) for 12 weeks.
The primary outcome measure, laughing and crying episodes (Figure 1), was statistically significantly lower in each dextromethorphan/quinidine arm compared to placebo, based on an analysis of the sums of the episode counts over the double-blind phase. The secondary endpoint was the Center for Neurologic Studies Lability Scale (CNS-LS) a seven-item self-report questionnaire with 3 items assessing crying and 4 assessing laughter. CNS-LS was analyzed based on the difference between the mean scores on day 84 and baseline, and was also statistically significantly lower in each dextromethorphan/quinidine arm compared to placebo (Figure 2). There were no clinically im
