(dye VAL proe ex)
Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures; monotherapy and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures
Depakote ‚ ®, Depakote ‚ ® ER: Mania associated with bipolar disorder; migraine prophylaxis
Hypersensitivity to divalproex, derivatives, or any component of the formulation; hepatic disease or significant impairment; urea cycle disorders
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Equivalent oral dosages of divalproex and valproic acid deliver the same quantities of valproate ion.
Seizures: Oral: Administer doses >250 mg/day in divided doses.
Simple and complex absence seizure: Initial: 15 mg/kg/day; increase by 5-10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maximum: 60 mg/kg/day.
Complex partial seizure: Initial: 10-15 mg/kg/day; increase by 5-10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maximum: 60 mg/kg/day.
Note: Regular release and delayed release formulations are usually given in 2-4 divided doses/day; extended release formulation (Depakote ‚ ® ER) is usually given once daily. Conversion to Depakote ‚ ® ER from a stable dose of Depakote ‚ ® may require an increase in the total daily dose between 8% and 20% to maintain similar serum concentrations.
Mania: Oral:
Depakote ‚ ® tablet: Initial: 750 mg/day in divided doses; dose should be adjusted as rapidly as possible to desired clinical effect; maximum recommended dosage: 60 mg/kg/day
Depakote ‚ ® ER: Initial: 25 mg/kg/day given once daily; dose should be adjusted as rapidly as possible to desired clinical effect; maximum recommended dose: 60 mg/kg/day.
Migraine prophylaxis: Oral:
Depakote ‚ ® tablet: 250 mg twice daily; adjust dose based on patient response, up to 1000 mg/day
Depakote ‚ ® ER: 500 mg once daily for 7 days, then increase to 1000 mg once daily; adjust dose based on patient response; usual dosage range: 500-1000 mg/day
Diabetic neuropathy (off-label use): Oral: 500-1200 mg/day (Bril, 2011)
Initiate at lower doses; dose escalation should be managed more slowly (in persons of advanced age). Refer to adult dosing.
Equivalent oral dosages of divalproex and valproic acid deliver the same quantities of valproate ion.
Seizures: Oral:
Simple and complex absence seizures: Refer to adult dosing. Larger maintenance doses may be required in younger children.
Complex partial seizures: Children ≥10 years: Refer to adult dosing. Larger maintenance doses may be required in younger children.
Note: Depakote ‚ ® ER is not recommended for use in children <10 years of age.
Migraine prophylaxis: Oral: Children ≥12 years: Refer to adult dosing.
A 27% reduction in clearance of unbound valproate is seen in patients with CrCl <10 mL/minute. Hemodialysis reduces valproate concentrations by 20%, therefore, no dose adjustment is needed in patients with renal failure. Protein binding is reduced, monitoring only total valproate concentrations may be misleading.
Dosage reduction is required. Clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2- to 2.6-fold increase in the unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal. Use is contraindicated in severe impairment.
Depakote ‚ ® ER: Swallow whole; do not crush or chew. Patients who need dose adjustments smaller than 500 mg/day for migraine prophylaxis should be changed to Depakote ‚ ® delayed release tablets.
Depakote ‚ ® Sprinkle capsules may be swallowed whole or open capsule and sprinkle on small amount (1 teaspoonful) of soft food and use immediately (do not store or chew).
Hazardous agent; use appropriate precautions for handling and disposal (NIOSH, 2012).
Divalproex may cause GI upset; take with large amount of water or food to decrease GI upset. May need to split doses to avoid GI upset.
Depakote ‚ ® Sprinkle capsule contents may be mixed with semisolid food (eg, applesauce or pudding) in patients having difficulty swallowing; particles should be swallowed and not chewed.
Depakote ‚ ® tablet: Store below 30 ‚ °C (86 ‚ °F).
Depakote ‚ ® Sprinkles: Store below 25 ‚ °C (77 ‚ °F).
Depakote ‚ ® ER: Store at controlled room temperature of 25 ‚ °C (77 ‚ °F).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, sprinkle, oral: 125 mg [strength expressed as valproic acid]
Depakote ‚ ® Sprinkle: 125 mg [strength expressed as valproic acid]
Tablet, delayed release, oral: 125 mg [strength expressed as valproic acid], 250 mg [strength expressed as valproic acid], 500 mg [strength expressed as valproic acid]
Depakote ‚ ®: 125 mg, 250 mg, 500 mg [strength expressed as valproic acid]
Tablet, extended release, oral: 250 mg [strength expressed as valproic acid], 500 mg [strength expressed as valproic acid]
Depakote ‚ ® ER: 250 mg, 500 mg [strength expressed as valproic acid]
Barbiturates: Valproate Products may increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products. Monitor therapy
CarBAMazepine: Valproate Products may increase serum concentrations of the active metabolite(s) of CarBAMazepine. Parent carbamazepine concentrations may be increased, decreased, or unchanged. CarBAMazepine may decrease the serum concentration of Valproate Products. Monitor therapy
Carbapenems: May decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Consider therapy modification
ChlorproMAZINE: May increase the serum concentration of Valproate Products. Monitor therapy
Cosyntropin: May enhance the hepatotoxic effect of Valproate Products. Management: Avoid concomitant use of Synacthen Depot (dosage form available in Canada) with valproic acid. Avoid combination
Ethosuximide: May decrease the serum concentration of Valproate Products. Valproate Products may increase the serum concentration of Ethosuximide. Monitor therapy
Felbamate: May increase the serum concentration of Valproate Products. Consider therapy modification
Fosphenytoin-Phenytoin: Valproate Products may decrease the protein binding of Fosphenytoin-Phenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products. Monitor therapy
GuanFACINE: May increase the serum concentration of Valproate Products. Monitor therapy
LamoTRIgine: Valproate Products may enhance the adverse/toxic effect of LamoTRIgine. Valproate Products may increase the serum concentration of LamoTRIgine. Consider therapy modification
Lesinurad: Valproate Products may increase the serum concentration of Lesinurad. Avoid combination
LORazepam: Valproate Products may increase the serum concentration of LORazepam. Consider therapy modification
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification
Methylfolate: May decrease the serum concentration of Valproate Products. Monitor therapy
Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy
Minoxidil (Systemic): Valproate Products may increase the serum concentration of Minoxidil (Systemic). Monitor therapy
OLANZapine: Valproate Products may decrease the serum concentration of OLANZapine. Monitor therapy
Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy
OXcarbazepine: Valproate Products may decrease the serum concentration of OXcarbazepine. Monitor therapy
Paliperidone: Valproate Products may increase the serum concentration of Paliperidone. Monitor therapy
Primidone: Valproate Products may decrease the metabolism of Primidone. More specifically, the metabolism of phenobarbital, primidones primary active metabolite, may be decreased. Primidone may increase the serum concentration of Valproate Products. Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Valproate Products. Monitor therapy
RifAMPin: May decrease the serum concentration of Valproate Products. Consider therapy modification
RisperiDONE: Valproate Products may enhance the adverse/toxic effect of RisperiDONE. Generalized edema has developed. Monitor therapy
Rufinamide: Valproate Products may increase the serum concentration of Rufinamide. Management: Initiate rufinamide at a dose less than 10 mg/kg/day (children) or 400 mg/day (adults) in patients receiving valproic acid. In patients receiving rufinamide, initiate valproic acid at a low dose and titrate based on clinical response. Consider therapy modification
Salicylates: May increase the serum concentration of Valproate Products. Monitor therapy
Sodium Oxybate: Valproate Products may increase the serum concentration of Sodium Oxybate. Management: Consider a sodium oxybate dose reduction of at least 20% if combined with valproic acid. Consider therapy modification
Temozolomide: Valproate Products may enhance the adverse/toxic effect of Temozolomide. Valproate Products may increase the serum concentration of Temozolomide. Monitor therapy
Topiramate: May enhance the adverse/toxic effect of Valproate Products. Monitor therapy
Tricyclic Antidepressants: Valproate Products may increase the serum concentration of Tricyclic Antidepressants. Monitor therapy
Urea Cycle Disorder Agents: Valproate Products may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Valproate Products may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Monitor therapy
Vorinostat: Valproate Products may enhance the thrombocytopenic effect of Vorinostat. This may increase the risk of gastrointestinal bleeding. Monitor therapy
Zidovudine: Valproate Products may increase the serum concentration of Zidovudine. Monitor therapy
Liver enzymes (at baseline and during therapy), CBC with platelets (baseline and periodic intervals), PT/PTT (especially prior to surgery), serum ammonia (with symptoms of lethargy, mental status change), serum valproate levels (trough for therapeutic levels); suicidality (eg, suicidal thoughts, depression, behavioral changes)
False-positive result for urine ketones
>10%:
Central nervous system: Headache ( ≤31%), somnolence ( ≤30%), dizziness (12% to 25%), insomnia (>1% to 15%), nervousness (>1% to 11%), pain (1% to 11%)
Dermatologic: Alopecia (>1% to 24%)
Gastrointestinal: Nausea (15% to 48%), vomiting (7% to 27%), diarrhea (7% to 23%), abdominal pain (7% to 23%), dyspepsia (7% to 23%), anorexia (>1% to 12%)
Hematologic: Thrombocytopenia (1% to 24%; dose related)
Neuromuscular & skeletal: Tremor ( ≤57%), weakness (6% to 27%)
Ocular: Diplopia (>1% to 16%), amblyopia/blurred vision ( ≤12%)
Miscellaneous: Infection ( ≤20%), flu-like syndrome (12%)
1% to 10%:
Cardiovascular: Peripheral edema (>1% to 8%), chest pain (>1% to <5%), edema (>1% to <5%), facial edema (>1% to <5%), hypertension (>1% to <5%), hypotension (>1% to <5%), orthostatic hypotension (>1% to <5%), palpitation (>1% to <5%), tachycardia (>1% to <5%), vasodilation(>1% to <5%), arrhythmia
Central nervous system: Ataxia (>1% to 8%), amnesia (>1% to 7%), emotional lability (>1% to 6%), fever (>1% to 6%), abnormal thinking ( ≤6%), depression (>1% to 5%), abnormal dreams (>1% to <5%), agitation (>1% to <5%), anxiety (>1% to <5%), catatonia (>1% to <5%), chills (>1% to <5%), confusion (>1% to <5%), coordination abnormal (>1% to <5%), hallucination (>1% to <5%), malaise (>1% to <5%), personality disorder (>1% to <5%), speech disorder (>1% to <5%), tardive dyskinesia (>1% to <5%), vertigo (>1% to <5%), euphoria (1%), hypoesthesia (1%)
Dermatologic: Rash (>1% to 6%), bruising (>1% to 5%), discoid lupus erythematosus (>1% to <5%), dry skin (>1% to <5%), furunculosis (>1% to <5%), petechia (>1% to <5%), pruritus (>1% to <5), seborrhea (>1% to <5%)
Endocrine & metabolic: Amenorrhea (>1% to <5%), dysmenorrhea (>1% to <5%), metrorrhagia (>1% to <5%), hypoproteinemia
Gastrointestinal: Weight gain (4% to 9%), weight loss (6%), appetite increased ( ≤6%), constipation (>1% to 5%), xerostomia (>1% to 5%), eructation (>1% to <5%), fecal incontinence (>1% to <5%), flatulence (>1% to <5%), gastroenteritis (>1% to <5%), glossitis (>1% to <5%), hematemesis (>1% to <5%), pancreatitis (>1% to <5%), periodontal abscess (>1% to <5%), stomatitis (>1% to <5%), taste perversion (>1% to <5%), dysphagia, gum hemorrhage, mouth ulceration
Genitourinary: Cystitis (>1% to 5%), dysuria (>1% to 5%), urinary frequency (>1% to <5%), urinary incontinence (>1% to <5%), vaginal hemorrhage (>1% to 5%), vaginitis (>1% to <5%)
Hepatic: ALT increased (>1% to <5%), AST increased (>1% to <5%)
Local: Injection site pain (3%), injection site reaction (2%), injection site inflammation (1%)
Neuromuscular & skeletal: Back pain ( ≤8%), abnormal gait (>1% to <5%), arthralgia (>1% to <5%), arthrosis (>1% to <5%), dysarthria (>1% to <5%), hypertonia (>1% to <5%), hypokinesia (>1% to <5%), leg cramps (>1% to <5%), myalgia (>1% to <5%), myasthenia (>1% to <5%), neck pain (>1% to <5%), neck rigidity (>1% to <5%), paresthesia (>1% to <5%), reflex increased (>1% to <5%), twitching (>1% to <5%)
Ocular: Nystagmus (1% to 8%), dry eyes (>1% to 5%), eye pain (>1% to 5%), abnormal vision (>1% to <5%), conjunctivitis (>1% to <5%)
Otic: Tinnitus (1% to 7%), ear pain (>1% to 5%), deafness (>1% to <5%), otitis media (>1% to <5%)
Respiratory: Pharyngitis (2% to 8%), bronchitis (5%), rhinitis (>1% to 5%), dyspnea (1% to 5%), cough (>1% to <5%), epistaxis (>1% to <5%), pneumonia (>1% to <5%), sinusitis (>1% to <5%)
Miscellaneous: Diaphoresis (1%), hiccups
<1% (Limited to important and/or life-threatening): Aggression, agranulocytosis, allergic reaction, anaphylaxis, anemia, aplastic anemia, asterixis, behavioral deterioration, bilirubin increased, bleeding time altered, bone marrow suppression, bone pain, bradycardia, breast enlargement, cutaneous vasculitis, carnitine decreased, cerebral atrophy (reversible), coma (rare), dementia, encephalopathy (rare), enuresis, eosinophilia, erythema multiforme, Fanconi-like syndrome (rare, in children), galactorrhea, hematoma formation, hemorrhage, hepatic failure, hepatotoxicity, hostility, hyperactivity, hyperammonemia, hyperammonemic encephalopathy (in patients with UCD), hyperglycinemia, hypersensitivity reactions (severe, with multiorgan dysfunction), hypofibrinogenemia, hyponatremia, hypothermia, inappropriate ADH secretion, intermittent porphyria, LDH increased, leukopenia, lupus, lymphocytosis, macrocytosis, menstrual irregularities, pancytopenia parkinsonism, parotid gland swelling, photosensitivity, platelet aggregation inhibited, polycystic ovary disease (rare), psychosis, seeing spots before the eyes," Stevens-Johnson syndrome, suicidal behavior/ideation, thyroid function tests abnormal, toxic epidermal necrolysis (rare), urinary tract infection
Protein binding in renal failure patients is substantially reduced.
Cl may be decreased and unbound fraction of valproate may be increased.
Intrinsic Cl is reduced 39%; the free fraction is increased 44%.
Children between 3 and 10 yr of age have a 50% higher Cl than adults. Older than the age of 10 yr, pharmacokinetic parameters in children approximate those of adults.
Concerns related to adverse effects:
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
- Hepatic failure: [U.S. Boxed Warning]: Hepatic failure resulting in fatalities has occurred in patients; children <2 years of age are at considerable risk. Other risk factors include organic brain disease, mental retardation with severe seizure disorders, congenital metabolic disorders, and patients on multiple anticonvulsants. Hepatotoxicity has usually been reported within 6 months of therapy initiation. Monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; discontinue immediately with signs/symptom of significant or suspected impairment. Liver function tests should be performed at baseline and at regular intervals after initiation of therapy, especially within the first 6 months. Hepatic dysfunction may progress despite discontinuing treatment. Should only be used as monotherapy in children <2 years of age and patients at high risk for hepatotoxicity.
- Hyperammonemia/encephalopathy: Hyperammonemia and/or encephalopathy, sometimes fatal, has been reported following the initiation of divalproex therapy and may be present with normal transaminase levels. Ammonia levels should be measured in patients who develop unexplained lethargy and vomiting, or changes in mental status or in patients who present with hypothermia. Discontinue therapy if ammonia levels are increased and evaluate for possible urea cycle disorder (UCD). Contraindicated in patients with UCD. Evaluation of UCD should be considered for the following patients prior to the start of therapy: History of unexplained encephalopathy or coma; encephalopathy associated with protein load; pregnancy or postpartum encephalopathy; unexplained mental retardation; history of elevated plasma ammonia or glutamine; history of cyclical vomiting and lethargy; episodic extreme irritability, ataxia; low BUN or protein avoidance; family history of UCD or unexplained infant deaths (particularly male); or signs or symptoms of UCD (hyperammonemia, encephalopathy, respiratory alkalosis).
- Hypothermia: Hypothermia (unintentional drop in core body temperature to <35 ‚ °C/95 ‚ °F) has been reported with divalproex therapy; may or may not be associated with hyperammonemia; may also occur with concomitant topiramate therapy.
- Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions have rarely been reported with some antiepileptic drugs including divalproex therapy in adults and children; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; discontinuation and conversion to alternate therapy may be required.
- Pancreatitis: [U.S. Boxed Warning]: Cases of life-threatening pancreatitis, occurring at the start of therapy or following years of use, have been reported in adults and children. Some cases have been hemorrhagic with rapid progression of initial symptoms to death. Promptly evaluate symptoms of abdominal pain, nausea, vomiting, and/or anorexia; should generally be discontinued if pancreatitis is diagnosed.
- Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
- Thrombocytopenia: May cause severe thrombocytopenia (may be dose-related), inhibition of platelet aggregation, and bleeding. In some cases, platelet counts may be normalized with continued treatment, however, reduce dose or discontinue drug if patient develops evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation. Evaluate platelet counts prior to initiating therapy and periodically thereafter.
- Tremors: May indicate overdosage.
Disease-related concerns:
- Hepatic impairment: Contraindicated with severe impairment.
Concurrent drug therapy issues:
- Carbapenem antibiotics: Concomitant use may reduce valproic acid levels to subtherapeutic levels; monitor levels frequently and consider alternate therapy if levels drop significantly or lack of seizure control occurs.
- Clonazepam: Concomitant use with clonazepam may induce absence status.
- Topiramate: Concomitant use with topiramate has been associated with hyperammonemia and hypothermia with or without encephalopathy.
Special populations:
- Elderly: Use with caution as elderly patients may be more sensitive to sedating effects; dose adjustment may be necessary.
- Pregnancy: [U.S. Boxed Warning]: May cause teratogenic effects such as neural tube defects (eg, spina bifida). Use in women of childbearing potential requires that benefits of use in mother be weighed against the potential risk to fetus, especially when used for conditions not associated with permanent injury or risk of death (eg, migraine).
Special handling:
- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH, 2012).
Other warnings/precautions:
- Viral replication: In vitro studies have suggested divalproex stimulates the replication of HIV and CMV viruses under experimental conditions. The clinical consequence of this is unknown, but should be considered when monitoring affected patients.
- Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
D
[U.S. Boxed Warning]: May cause teratogenic effects such as neural tube defects (eg, spina bifida). Teratogenic effects have been reported in animals and humans. Valproic acid crosses the placenta. Neural tube, cardiac, facial (characteristic pattern of dysmorphic facial features), skeletal, multiple other defects reported. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Information from the North American Antiepileptic Drug Pregnancy Registry notes a fourfold increase in congenital malformations with exposure to valproic acid monotherapy during the 1st trimester of pregnancy when compared to monotherapy with other antiepileptic drugs (AED). The risk of neural tube defects is ~1% to 2% (general population risk estimated to be 0.14% to 0.2%). The effect of folic acid supplementation to decrease this risk is unknown, however, folic acid supplementation is recommended for all women contemplating pregnancy. An information sheet describing the teratogenic potential is available from the manufacturer.
Nonteratogenic effects have also been reported. Afibrinogenemia leading to fatal hemorrhage and hepatotoxicity have been noted in case reports of infants following in utero exposure to valproic acid. Developmental delay, autism and/or autism spectrum disorder have also been reported. In a prospective cohort study conducted in the U.S. and the United Kingdom, a lower Differential Ability Scale ([D.A.S.]; a battery of tests which measure cognitive development in children) score was observed in children 3 years of age with prenatal exposure to valproate compared to children with prenatal exposure to other antiepileptics (lamotrigine, carbamazepine, or phenytoin). Use in women of childbearing potential requires that benefits of use in mother be weighed against the potential risk to fetus, especially when used for conditions not associated with permanent injury or risk of death (eg, migraine).
Patients exposed to valproic acid during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Causes increased availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to brain neurons or may enhance the action of GABA or mimic its action at postsynaptic receptor sites
Total valproate: 11 L/1.73 m2; Free valproate: 92 L/1.73 m2
Extensively hepatic via glucuronide conjugation and mitochondrial beta-oxidation. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Urine (30% to 50% as glucuronide conjugate, 3% as unchanged drug)
Serum: Depakote ‚ ® tablet: ~4 hours; Depakote ‚ ® ER: 4-17 hours
Increased in neonates and with liver disease; Children >2 months: 7-13 hours; Adults: 9-16 hours
Dose dependent: 80% to 90%; decreased in the elderly and with hepatic or renal dysfunction
Oral: Do not crush or chew capsule or enteric-coated pill. While using this medication, do not use alcohol. Maintain adequate hydration, unless instructed to restrict fluid intake. You may experience nervousness, decreased appetite, insomnia, headache, sleepiness, dizziness, visual changes, and hair loss. Report suicide ideation or depression; alterations in menstrual cycle; abdominal cramps, unresolved diarrhea, vomiting, or constipation; skin rash; tremors; unusual bruising or bleeding; blood in urine, stool, or vomitus; malaise; weakness; facial swelling; yellowing of skin or eyes; persistent abdominal pain; excessive sedation; change in mental status; extreme lethargy; or restlessness.