What happens if I overdose Pendine?
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Proper storage of Pendine capsules:
Store Pendine capsules between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Pendine capsules out of the reach of children and away from pets.
Overdose of Pendine in details
A lethal dose of Pendine was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.
Acute oral overdoses of Pendine up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy, and diarrhea were observed. All patients recovered with supportive care. Coma, resolving with dialysis, has been reported in patients with chronic renal failure who were treated with Pendine.
Pendine can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.
If overexposure occurs, call your poison control center at 1-800-222-1222.
What should I avoid while taking Pendine?
- Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Pendine without first talking to your healthcare provider. Taking Pendine with alcohol or medicines that cause sleepiness or dizziness may make you sleepiness or dizziness worse.
- Do not operate heavy machines or do other dangerous activities until you know how Pendine affects you. Pendine can slow your thinking and motor skills.
Pendine warnings
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Pendine. Some of these reactions 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, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Pendine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Effects on Driving and Operating Heavy Machinery
Patients taking Pendine should not drive until they have gained sufficient experience to assess whether Pendine impairs their ability to drive. Driving performance studies conducted with a prodrug of Pendine (Pendine enacarbil tablet, extended release) indicate that Pendine may cause significant driving impairment. Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by Pendine, can be imperfect. The duration of driving impairment after starting therapy with Pendine is unknown. Whether the impairment is related to somnolence or other effects of Pendine is unknown.
Moreover, because Pendine causes somnolence and dizziness, patients should be advised not to operate complex machinery until they have gained sufficient experience on Pendine to assess whether Pendine impairs their ability to perform such tasks.
Somnolence/Sedation and Dizziness
During the controlled epilepsy trials in patients older than 12 years of age receiving doses of Pendine up to 1800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving Pendine compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia. In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of Pendine in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.
During the controlled trials in patients with post-herpetic neuralgia, somnolence and dizziness were reported at a greater rate compared to placebo in patients receiving Pendine, in dosages up to 3600 mg per day: i.e., 21% in Pendine-treated patients versus 5% in placebo-treated patients for somnolence and 28% in Pendine-treated patients versus 8% in placebo-treated patients for dizziness. Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of Pendine.
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.
In the placebo-controlled epilepsy studies in patients >12 years of age, the incidence of status epilepticus in patients receiving Pendine was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with Pendine across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with Pendine is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with Pendine.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Pendine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
| Indication | Placebo Patients with Events Per1000 Patients | Drug Patients with Events Per1000 Patients | Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients | Risk Difference Additional Drug: Patients with Events Per 1000 Patients |
| Epilepsy | 1.0 | 3.4 | 3.5 | 2.4 |
| Psychiatric | 5.7 | 8.5 | 1.5 | 2.9 |
| Other | 1.0 | 1.8 | 1.9 | 0.9 |
| Total | 2.4 | 4.3 | 1.8 | 1.9 |
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Pendine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Neuropsychiatric Adverse Reactions (Pediatric Patients 3-12 Years of Age)
Pendine use in pediatric patients with epilepsy 3-12 years of age is associated with the occurrence of central nervous system related adverse reactions. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the Pendine-treated patients, most of the reactions were mild to moderate in intensity.
In controlled clinical epilepsy trials in pediatric patients 3–12 years of age, the incidence of these adverse reactions was: emotional lability 6% (Pendine-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these reactions, a report of hostility, was considered serious. Discontinuation of Pendine treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of Pendine-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability.
Tumorigenic Potential
In an oral carcinogenicity study, Pendine increased the incidence of pancreatic acinar cell tumors in rats. The clinical significance of this finding is unknown. Clinical experience during Pendine’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of Pendine. Without knowledge of the background incidence and recurrence in a similar population not treated with Pendine, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.
Sudden and Unexplained Death in Patients with Epilepsy
During the course of premarketing development of Pendine, 8 sudden and unexplained deaths were recorded among a cohort of 2203 epilepsy patients treated (2103 patient-years of exposure) with Pendine.
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Pendine (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the Pendine program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the Pendine cohort and the accuracy of the estimates provided.
Laboratory Tests
Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of Pendine. The value of monitoring Pendine blood concentrations has not been established. Pendine may be used in combination with other antiepileptic drugs without concern for alteration of the blood concentrations of Pendine or of other antiepileptic drugs.
What should I discuss with my healthcare provider before taking Pendine?
Before taking Pendine, tell your healthcare provider if you:
- have or have had depression, mood problems or suicidal thoughts or behavior
- have seizures
- have kidney problems or get kidney dialysis
- are pregnant or plan to become pregnant. It is not known if Pendine can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Pendine. You and your healthcare provider will decide if you should take Pendine while you are pregnant.
- If you become pregnant while taking Pendine, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs, including Pendine, the active ingredient in Pendine, during pregnancy. You can enroll in this registry by calling 1-888582-233-2334.
- are breastfeeding or plan to breastfeed. Pendine can pass into your breast milk. You and your healthcare provider should decide how you will feed your baby while you take Pendine.
Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins or herbal supplements.
Taking Pendine with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
Pendine precautions
Although there is no evidence of rebound seizures with Pendine, abrupt withdrawal of anticonvulsant agents in epileptic patients may precipitate status epilepticus. When dose reduction, discontinuation or substitution of alternative anticonvulsant medication is needed, this should be done gradually over a minimum period of 1 week.
Pendine is not generally considered effective in the treatment of absence seizures and may exacerbate these seizures in some patients. Consequently, Pendine should be used with caution in patients who have mixed seizure disorders that include absence seizures.
Psychotic episodes have been reported with the use of Pendine in some patients, with and rarely without, a history of psychotic illness. Most of these events resolved with discontinuation of therapy. Patients taking Pendine can experience mood and behavioural disturbances.
Effects on the Ability to Drive or Operate Machinery: Pendine may cause somnolence, dizziness and other CNS symptoms. Therefore, patients should be cautioned about driving or operating machinery until they are reasonably certain that this therapy does not affect their ability to engage in such activities.
Use in pregnancy & lactation: Safe use of Pendine in human pregnancy has not been established.
Reproduction studies in mice, rats or rabbits at doses of up to 50, 30 and 25 times respectively, the daily human dose of 3600 mg revealed no evidence of impaired fertility or harm to the fetus due to Pendine administration. However, there are no well controlled studies in pregnant women. Therefore, Pendine should be used during pregnancy only if the potential benefits clearly outweigh the potential risks.
Pendine is excreted in human milk but the effect on the nursing infant is unknown. Because of the potential for serious adverse reactions in nursing infants from Pendine, a decision should made whether to discontinue nursing or to discontinue Pendine, taking into account the importance of Pendine to the mother.
Use in children: Safety of Pendine in children <12 years is not established.
What happens if I miss a dose of Pendine?
Take the missed dose as soon as you remember. Be sure to take the medicine with food. 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.
References
- DailyMed. "GABAPENTIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- DrugBank. "gabapentin". http://www.drugbank.ca/drugs/DB00996 (accessed September 17, 2018).
- MeSH. "Excitatory Amino Acid Antagonists". https://www.ncbi.nlm.nih.gov/mesh/68... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
