LAMOTRIGINE WITHDRWAL AND TAPERING HELP

Lamotrigine (Lamictal) is marketed throughout the world as Lamotrigine, an anticonvulsant drug used for epilepsy and bipolar and off-label for depression, anxiety and other issues. Lamictal was the first drug (other than Lithium) approved for bi-polar. Approximately 10% of patients taking Lamotrigine suffer what is deemed a 'safe rash' that is actually an allergic reaction. Lamotrigine prescribing information has a black-box warning regarding life-threatening skin reactions that primarily occur in the first 2-8 weeks of therapy, or during withdrawal if Lamotrigine is stopped too quickly. 

In December 1994 Lamictal / Lamotrigine was approved by the FDA as a treatment for partial seizures in adult patients; in 1998 it was approved for pediatric patients over 2 years of age; and in 2003 Lamictal was approved for Bipolar disorder.

Approximately 10% of patients taking Lamictal suffer what is deemed a 'safe rash' that is actually an allergic reaction. Lamictal prescribing information has a black-box warning regarding life-threatening skin reactions that primarily occur in the first 2-8 weeks of therapy, or during withdrawal if Lamictal is stopped too quickly.

Evidence has shown that women are more likely to have side effects from Lamicital than men. Female hormones decrease serum levels of Lamictal while there is a significant increase in the follicle stimulating hormone (FSH) and luteninizing hormone (LH) from Lamictal. FSH is secreted by the pineal gland and regulates estrogen and progesterone within the ovaries in women and the sperm count in men.

Approximately 7% of patients experience a 'alerting effect' that causes intolerable insomnia. More severe side effects include aseptic meningitis and Stevens-Johnson syndrome. Meningitis is an inflammation of the protective membranes that cover the brain and spinal cord and Stevens Johnson syndrome is a serious condition where the skin of the patient literally burns from the inside out. Additionally, Lamictal binds to melanin-containing (pigment) tissues such as the iris of the eye. Long-term consequences of this are unknown at this time.

In 2010 the FDA warned doctors and patients regarding Lamictal's serious side effects, yet the drug remains on the market today.

Unless a life-threatening reaction to Lamictal is occurring, the drug should be tapered slowly due to the risk of seizure and debilitating withdrawal symptoms. Yet many find that even with a slow taper, Lamictal withdrawal symptoms interfere with every aspect of life.

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LAMOTRIGINE WITHDRAWAL SYMPTOMS MAY INCLUDE:

shaking, confusion, dizziness, sweating, severe headache, insomnia, anxiety, burning or tingling sensations around the body, brain zaps / brain shivers, vertigo, light headedness, rushing noise in the head, agitation, negative, tearful, concentration problem, tremors, diarrhea, vomiting, reduced appetite, nightmares, excessive dreaming, gastrointestinal issues

LAMOTRIGINE SIDE EFFECTS MAY INCLUDE: 

fever, rash, backache, blurred vision, chest pain, trouble sleeping, dizzy, double vision, drowsiness, dry mouth, nausea, head pain, infection, quivering, low energy, stomach cramps, uncoordination, anger, mental impairment, toxic effect on brain or spinal cord, anxiety, confusion, diarrhea, indigestion, joint pain, neck pain, mood changed, loss of appetite, pain, eyesight issues, weight loss 

LAMOTRIGINE ADVERSE REACTIONS MAY INCLUDE: per PDR 

Severe: suicidal ideation, peptic ulcer, visual impairment, bronchospasm, hematemesis, Stevens-Johnson syndrome, exfoliative dermatitis, angioedema, toxic epidermal necrolysis, erythema multiforme, renal failure (unspecified), epididymitis, vasculitis, rhabdomyolysis, apnea, lupus-like symptoms, pancreatitis, disseminated intravascular coagulation (DIC), hepatic failure, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), myocarditis, aplastic anemia, red cell aplasia, pancytopenia, hemolytic anemia, agranulocytosis, aseptic meningitis, hemophagocytic lymphohistiocytosis 

Moderate: blurred vision, ataxia, chest pain (unspecified), constipation, contact dermatitis, depression, migraine, nystagmus, amnesia, hyperreflexia, peripheral edema, edema, dyspnea, vaginitis, hot flashes, lymphadenopathy, atopic dermatitis, hallucinations, aphasia, memory impairment, dyskinesia, hypertonia, akathisia, hostility, psychosis, dysarthria, euphoria, hypertension, palpitations, sinus tachycardia, peripheral vasodilation, orthostatic hypotension, myasthenia, dysphagia, elevated hepatic enzymes, gastritis, photophobia, conjunctivitis, leukopenia, impotence (erectile dysfunction), hematuria, ejaculation dysfunction, urinary incontinence, neuritis, dystonic reaction, dysphoria, delirium, hyperalgesia, hyperesthesia, choreoathetosis, hypotonia, hepatitis, melena, colitis, stomatitis, glossitis, erythema, eosinophilia, anemia, lymphocytosis, thrombocytopenia, dysuria, urinary retention , cystitis, hyperbilirubinemia, hypothyroidism, hyperglycemia, goiter, mania, confusion, amblyopia, esophagitis, neutropenia, hyponatremia, splenomegaly 

Mild: diplopia, vomiting, drowsiness, fever, dizziness, pharyngitis, nausea, rash, diarrhea, tremor, abdominal pain, asthenia, fatigue, back pain, cough, dyspepsia, dysmenorrhea, xerostomia, weight loss, diaphoresis, libido increase, agitation, irritability, emotional lability, hypoesthesia, hyporeflexia, arthralgia, myalgia, sinusitis, epistaxis, flatulence, weight gain, anorexia, increased urinary frequency, xerosis, vertigo, amenorrhea, libido decrease, hyperkinesis, malaise, paranoia, flushing, syncope, yawning, eructation, hypersalivation, gingivitis, appetite stimulation, tinnitus, urticaria, ecchymosis, menorrhagia, polyuria, acne vulgaris, alopecia, hirsutism, skin discoloration, hyperventilation, hiccups, parosmia, ptosis, maculopapular rash, leukocytosis, petechiae, nocturia, urinary urgency, headache, paresthesias, insomnia, anxiety, influenza, infection, rhinitis, pruritus, nasal congestion 

LAMOTRIGINE BOXED WARNINGS: per PDR:

Hemophagocytic lymphohistiocytosis, history of angioedema, serious rash

Lamotrigine use is contraindicated in patients who have demonstrated hypersensitivity to lamotrigine (e.g., rash, history of angioedema, acute urticaria, extensive pruritus, mucosal ulceration) or other life-threatening hypersensitivity or serious immune-related events. Due to life-threatening serious rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis), lamotrigine carries a boxed warning stating the drug should be discontinued if rash occurs at any time during treatment. It is important to note that discontinuation of lamotrigine may not prevent progression to a higher level of severity; therefore patients should be closely monitored. Age is the only factor currently known to predict the occurrence or severity of a rash, with pediatric patients at increased risk. Other possible but unproven factors include concurrent use of valproate, exceeding the initial recommended dose, or exceeding the recommended dose titration. Almost all cases of life-threatening rash have occurred within the first 2 to 8 weeks of treatment. However, a prolonged duration of therapy should not preclude the possibility of an association to the drug. Also, caution is advised when administering lamotrigine to patients with a history of rash or allergy to other anticonvulsants, since non-serious rashes have occurred 3 times more frequently in these patients during treatment with lamotrigine than in those without this history. Lamotrigine should not be resumed following prior discontinuation due to rash unless the benefits outweigh the risks. If the drug is reintroduced and it has been 5 half-lives or longer since the last dose, the manufacturer recommends reinitiating using initial dosing recommendations. Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Discontinue lamotrigine if an alternative etiology for the signs or symptoms cannot be established. Lamotrigine may also cause hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious uncontrolled immune system response that may result in hospitalization and death. Severe inflammation occurs throughout the body leading to severe problems with blood cells and organs throughout the body. HLH typically presents with a fever (greater than 101 degrees F) and rash. Other signs and symptoms may include enlarged liver with pain, tenderness, or unusual swelling over the liver area in the upper right belly, swollen lymph nodes, yellow skin or eyes, unusual bleeding, or nervous system problems (seizures, trouble walking, difficulty seeing, or other visual disturbances). A diagnosis may be established if 5 of the following symptoms from the HLH-2004 diagnostic criteria are present: fever or rash, enlarged spleen (splenomegaly), cytopenias, elevated concentrations of triglycerides or low blood concentrations of fibrinogen, high concentrations of blood ferritin, hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy, decreased or absent natural killer cell activity, and elevated blood concentrations of CD25 showing prolonged immune cell activation. Evaluate patients who present with fever or rash promptly, as early recognition is necessary to improve outcomes and reduce mortality. HLH may be confused with other serious immune-system reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

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According to the FDA regarding Lamictal / Lamotrigine Withdrawal:

Discontinuation Strategy in Bipolar Disorder: As with other AEDs, LAMICTAL / Lamotrigine should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL / Lamotrigine. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL / Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of LAMICTAL  / Lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.

Withdrawal Seizures: As with other AEDs, LAMICTAL / Lamotrigine should not be abruptly discontinued. 

In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (see DOSAGE AND ADMINISTRATION). 

REFERENCES:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf 

https://www.ncbi.nlm.nih.gov/pubmed/15804245

 https://www.ncbi.nlm.nih.gov/pubmed/11886370

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