Orphenadrine Citrate

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• Tachycardia: A noticeable increase in heart rate or palpitations.
• Urinary Hesitancy or Retention: Difficulty starting urination or the feeling that the bladder is not completely empty, particularly in older men with prostate issues.
• Constipation: Reduced bowel motility can lead to infrequent or difficult bowel movements.
• Nausea and Vomiting: Some patients experience gastrointestinal distress shortly after taking the dose.
• Headache: Ironically, while used for some headaches, it can cause a dull, generalized headache in some users.

• Hallucinations and Confusion: These are more common at higher doses or in elderly patients. They may involve seeing or hearing things that are not there.
• Excitation or Agitation: Some individuals may experience a paradoxical reaction where they feel hyperactive or restless rather than sedated.
• Syncope (Fainting): A sudden drop in blood pressure can lead to a brief loss of consciousness.
• Aplastic Anemia: Extremely rare cases of blood disorders have been reported, primarily with combination products containing other agents.

> Warning: Stop taking Orphenadrine and call your doctor immediately or seek emergency care if you experience any of the following:

• Anaphylaxis or Severe Allergic Reaction: Symptoms include hives, swelling of the face, lips, or throat, and difficulty breathing.
• Eye Pain or Vision Changes: This could indicate an undiagnosed case of narrow-angle glaucoma being exacerbated by the drug.
• Severe Urinary Retention: Complete inability to pass urine, which is a medical emergency.
• Seizures: Any twitching or loss of consciousness with shaking.
• Severe Tachycardia: A heart rate that feels dangerously fast or irregular.
• Mental/Mood Changes: Severe agitation, paranoia, or suicidal ideation.

Orphenadrine is not intended for long-term use. Prolonged use (months or years) can lead to:

• Tolerance: The body may become accustomed to the drug, requiring higher doses to achieve the same muscle-relaxing effect.
• Chronic Dry Mouth Complications: Long-term xerostomia can lead to an increase in dental cavities, gum disease, and oral yeast infections (thrush).
• Cognitive Decline: In older adults, chronic use of anticholinergic drugs has been linked in some observational studies to an increased risk of dementia and cognitive impairment.

There are currently no FDA black box warnings specifically for orphenadrine citrate. However, it carries significant warnings regarding its use in patients with certain pre-existing conditions like glaucoma or myasthenia gravis, which are discussed in the Contraindications section.

Report any unusual symptoms or side effects to your healthcare provider. You may also report side effects to the FDA at 1-800-FDA-1088.

For short-term use (the standard indication), extensive lab monitoring is usually not required. However, for patients on combination products or those with underlying health issues, healthcare providers may monitor:

• Liver Function Tests (LFTs): Especially if the drug is used for longer than 2 weeks or in patients with known hepatic issues.
• Renal Function: Monitoring creatinine and BUN levels in elderly patients or those with kidney disease.
• Intraocular Pressure: For patients at risk of glaucoma.
• Complete Blood Count (CBC): To monitor for rare blood dyscrasias associated with long-term use.

Orphenadrine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. This effect is magnified when the drug is combined with alcohol or other CNS depressants. Patients should not drive until they are certain the medication does not cause significant drowsiness or dizziness.

Alcohol must be avoided while taking orphenadrine. Alcohol increases the sedative effects of the drug, leading to extreme drowsiness, respiratory depression, and an increased risk of falls or accidents. The combination can also increase the risk of gastrointestinal bleeding if the orphenadrine is part of a combination product containing aspirin.

While orphenadrine is not typically associated with a severe withdrawal syndrome, it should not be stopped abruptly if it has been used at high doses for an extended period. A gradual taper under medical supervision may be recommended to prevent a rebound of muscle spasms or "anticholinergic rebound" symptoms (such as sweating, nausea, and headache).

> Important: Discuss all your medical conditions, especially any history of heart, eye, or bladder problems, with your healthcare provider before starting Orphenadrine.

• Cholinesterase Inhibitors: Drugs used for Alzheimer’s (e.g., donepezil, rivastigmine) work by increasing acetylcholine. Orphenadrine blocks acetylcholine, thereby reducing the effectiveness of these dementia treatments.
• CYP Enzyme Inducers/Inhibitors: Since orphenadrine is metabolized by CYP2B6 and CYP3A4, drugs that inhibit these enzymes (like fluoxetine or clarithromycin) can increase orphenadrine levels, while inducers (like rifampin) can decrease its efficacy.

• Alcohol: As noted, alcohol significantly increases CNS depression and should be strictly avoided.
• Caffeine: If taking a combination product that already contains caffeine, additional intake of coffee, tea, or energy drinks may lead to jitters, insomnia, and tachycardia.
• Grapefruit Juice: While not as significant as with other drugs, grapefruit juice can inhibit CYP3A4, potentially slowing the metabolism of orphenadrine.

• Kava Kava and Valerian Root: These herbal supplements have sedative properties and can cause excessive drowsiness when taken with orphenadrine.
• St. John’s Wort: This can induce the CYP enzymes responsible for breaking down orphenadrine, potentially making the medication less effective.
• Anticholinergic Herbs: Herbs like belladonna or henbane should be avoided due to additive toxicity.

Orphenadrine is not known to significantly interfere with most common laboratory tests. However, if you are taking the combination product containing aspirin, it may affect urine glucose tests (giving false negatives in some methods) or stool occult blood tests.

For each major interaction, the mechanism usually involves either pharmacodynamic synergism (where two drugs do the same thing to the body, doubling the effect) or pharmacokinetic interference (where one drug changes how the other is absorbed or metabolized). Management typically involves avoiding the combination or adjusting the dose while monitoring for toxicity.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers and allergy meds.

In these cases, a healthcare provider will perform a careful risk-benefit analysis:

• Cardiac Arrhythmias: Because the drug can increase heart rate, it may trigger or worsen existing irregular heartbeats.
• Coronary Artery Disease: The increased cardiac workload from a faster heart rate can be dangerous for those with restricted blood flow to the heart.
• Mild to Moderate Renal or Hepatic Impairment: Requires lower dosing and frequent monitoring.
• History of Drug Abuse: While not highly addictive, its sedative and occasionally hallucinogenic effects at high doses mean it should be used cautiously in those with a history of substance use disorders.

Patients who are allergic to diphenhydramine (Benadryl) may have a cross-sensitivity to orphenadrine due to their similar chemical structures. If you have had a severe reaction to Benadryl, inform your doctor before starting orphenadrine.

> Important: Your healthcare provider will evaluate your complete medical history, including any "hidden" conditions like undiagnosed eye pressure issues, before prescribing Orphenadrine.

It is not known whether orphenadrine is excreted in human milk. However, many drugs in this class do pass into breast milk. Because of the potential for serious adverse reactions in nursing infants (such as extreme sleepiness or feeding difficulties), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Orphenadrine is not approved for use in children under 18 years of age. The safety profile has not been established in this group. Pediatric patients may be more susceptible to the CNS side effects, including seizures and paradoxical excitation.

Use in the elderly (65 years and older) requires extreme caution.

• Fall Risk: Dizziness and sedation significantly increase the risk of falls and fractures.
• Cognitive Effects: Increased risk of confusion and delirium.
• Clearance: Reduced kidney and liver function in the elderly means the drug stays in the system longer, increasing the "anticholinergic burden."
• Beers Criteria: It is explicitly listed as a drug to avoid in the elderly whenever possible.

In patients with chronic kidney disease, the excretion of orphenadrine metabolites is delayed. While specific dose-adjustment tables are not available, healthcare providers typically start at the lowest possible dose (e.g., 100 mg once daily instead of twice) and monitor for signs of toxicity like blurred vision or urinary retention.

Since the liver is the primary site of metabolism via CYP enzymes, patients with hepatic impairment (Child-Pugh Class B or C) are at high risk for drug accumulation. Frequent monitoring of liver enzymes and clinical status is necessary. If severe liver failure is present, the drug may be contraindicated.

> Important: Special populations require individualized medical assessment. Always disclose your full health status, including pregnancy or plans to become pregnant, to your healthcare team.

• Onset of Action: For the oral immediate-release form, effects begin within 1 hour. For the injectable form, onset is within 5-15 minutes.
• Duration: The therapeutic effect of an ER tablet lasts approximately 12 hours.
• Tolerance: While physical dependence is rare, pharmacological tolerance to the sedative and anticholinergic effects can develop with several weeks of continuous use.

| Parameter | Value |

|---|---|

| Bioavailability | ~90% (Oral) |

| Protein Binding | 95% |

| Half-life | 13–20 hours |

| Tmax | 2 hours (IR), 6-8 hours (ER) |

| Metabolism | Hepatic (CYP2B6, 2D6, 3A4) |

| Excretion | Renal (8% unchanged), Fecal (trace) |

• Molecular Formula: C18H23NO • C6H8O7 (Citrate salt)
• Molecular Weight: 461.5 g/mol (Citrate form)
• Solubility: Sparingly soluble in water, slightly soluble in alcohol.
• Structure: It is the ortho-methyl analog of diphenhydramine. It consists of a tertiary amine and an ether linkage.

Orphenadrine is classified as a skeletal muscle relaxant and an anticholinergic. Within the therapeutic area of musculoskeletal medicine, it is grouped with other centrally acting agents. Unlike baclofen (a GABA-B agonist) or tizanidine (an alpha-2 agonist), orphenadrine’s primary utility stems from its anticholinergic and NMDA-modulating profile.