WARNINGS
LODOSYN (Carbidopa) has no antiparkinsonian effect when given alone. It is indicated
for use with carbidopa-levodopa or levodopa. LODOSYN (Carbidopa) does not decrease
adverse reactions due to central effects of levodopa.
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are being treated with levodopa alone, the two drugs should be given at the same time. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with LODOSYN (Carbidopa) and levodopa in combination. Start with no more than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when given without LODOSYN (Carbidopa). See the DOSAGE AND ADMINISTRATION section before initiating therapy.
The addition of LODOSYN with levodopa or carbidopa-levodopa reduces the peripheral
effects (nausea, vomiting) due to decarboxylation of levodopa; however, LODOSYN does
not decrease the adverse reactions due to the central effects of levodopa. Because LODOSYN permits more levodopa to reach the brain and more dopamine to be formed,
certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary
movements), may occur at lower dosages and sooner with levodopa in combination with
LODOSYN than with levodopa alone.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have
reported suddenly falling asleep without prior warning of sleepiness while engaged in activities
of daily living (includes operation of motor vehicles). Some of these episodes resulted in
automobile accidents. Although many of these patients reported somnolence while on
dopaminergic medications, some did perceive that they had no warning signs, such as excessive
drowsiness, and believed that they were alert immediately prior to the event. Some patients
reported these events one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing
pre-existing somnolence, although some patients may not give such a history. For this reason,
prescribers should continually reassess patients for drowsiness or sleepiness especially since
some of the events occur after the start of treatment. Prescribers should be aware that patients
may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
sleepiness during specific activities. Patients who have already experienced somnolence or an
episode of sudden sleep onset should not participate in these activities during treatment with
LODOSYN when taking it with other carbidopa-levodopa products.
Before initiating treatment with LODOSYN, advise patients about the potential to develop
drowsiness and ask specifically about factors that may increase the risk for somnolence with
LODOSYN such as the use of concomitant sedating medications and the presence of sleep
disorders. Consider discontinuing LODOSYN in patients who report significant daytime
sleepiness or episodes of falling asleep during activities that require active participation (e.g.,
conversations, eating, etc.). If treatment with LODOSYN continues, patients should be advised
not to drive and to avoid other potentially dangerous activities that might result in harm if the
patients become somnolent. There is insufficient information to establish that dose reduction
will eliminate episodes of falling asleep while engaged in activities of daily living.
As with levodopa alone there is a possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
Hyperpyrexia and Confusion
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have
been reported in association with dose reductions or withdrawal of certain antiparkinsonian
agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release. Therefore, patients should be observed carefully when the dosage of levodopa or arbidopalevodopa is reduced abruptly or discontinued, especially if the patient is receiving
neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered
consciousness, mental status changes; other disturbances, such as autonomic dysfunction,
tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin, have been reported.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses
(e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the
clinical presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants,
such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has
not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and
renal function are recommended during extended concomitant therapy with LODOSYN and
levodopa, or with LODOSYN and carbidopa-levodopa or any combination of these drugs.
Impulse Control/Compulsive Behaviors
Postmarketing reports suggest that patients treated with anti-Parkinson medications can
experience intense urges to gamble, increased sexual urges, intense urges to spend money
uncontrollably, binge eating, and other intense urges. Patients may be unable to control these
urges while taking one or more of the medications that are used for the treatment of Parkinson’s
disease and that increase central dopaminergic tone, including Lodosyn taken with levodopa and
carbidopa. In some cases, although not all, these urges were reported to have stopped when the
dose of anti-Parkinson medications was reduced or discontinued. Because patients may not
recognize these behaviors as abnormal it is important for prescribers to specifically ask patients
or their caregivers about the development of new or increased gambling urges, sexual urges,
uncontrolled spending or other urges while being treated with Lodosyn. Physicians should
consider dose reduction or stopping Lodosyn or levodopa if a patient develops such urges while
taking Lodosyn with carbidopa/levodopa.
Hallucinations/Psychotic-Like Behavior
Hallucinations and psychotic like behavior have been reported with dopaminergic medications.
In general, hallucinations present shortly after the initiation of therapy and may be responsive to
dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser
extent sleep disorder (insomnia) and excessive dreaming. LODOSYN when taken with
carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking
and behavior may present with one or more symptoms, including paranoid ideation, delusions,
hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior,
agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with LODOSYN and
carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and
may decrease the effectiveness of LODOSYN.
Dyskinesia
LODOSYN (Carbidopa) may potentiate the dopaminergic side effects of levodopa and may
cause or exacerbate preexisting dyskinesia.
Depression
Patients treated with LODOSYN and carbidopa-levodopa should be observed carefully for the
development of depression with concomitant suicidal tendencies.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk
(2-to approximately 6-fold higher) of developing melanoma than the general population.
Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas
frequently and on a regular basis when using LODOSYN tablets for Parkinson’s disease.
Ideally, periodic skin examinations should be performed by appropriately qualified individuals
(e.g., dermatologists).
Information for Patients
It is important that LODOSYN with levodopa be taken at regular intervals according to the
schedule outlined by the health care provider. Caution patients not to change the prescribed
dosage regimen and not to add any additional antiparkinson medications, including other
carbidopa-levodopa preparations without first consulting a physician.
Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing
Interval. Tell patients to notify the prescriber if such response poses a problem to lifestyle.
Patients should be advised that occasionally dark color (red, brown, or black) may appear in
saliva, urine, or sweat after ingestion of LODOSYN and levodopa. Although the color appears
to be clinically insignificant, garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay
The absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in multivitamin tablets) may also reduce the amount of levodopa available in the body. The above factors may reduce the clinical effectiveness of the LODOSYN and levodopa therapy.
Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases
without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Advise patients to exercise caution while driving or operating machinery and that if
they have experience somnolence and/or sudden sleep onset, they must refrain from these
activities. (See WARNINGS, Falling Asleep During Activities of Daily Living and Somnolence
General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual
urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including LODOSYN and levodopa. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other intense urges while taking LODOSYN and levodopa. Physicians should consider dose reduction or stopping
Lodosyn and levodopa if a patient develops such urges while taking Lodosyn with carbidopa/levodopa (See
PRECAUTIONS, Impulse Control/Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during concomitant administration of carbidopa and levodopa than with levodopa alone.
Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for
urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will
not be altered by boiling the urine specimen. False-negative tests may result with the use of
glucose-oxidase methods of testing for glucosuria.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with LODOSYN (Carbidopa) given with levodopa or carbidopa-levodopa combination products.
Symptomatic postural hypotension has occurred when LODOSYN, given with levodopa or
carbidopa-levodopa combination products, was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with LODOSYN, given with or without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of
the antihypertensive drug may be required.
For patients receiving monoamine oxidase inhibitors (Type A or B), see
CONTRAINDICATIONS. Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see
CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with LODOSYN and levodopa or carbidopa-levodopa combination products should be carefully observed for loss of therapeutic response.
LODOSYN and iron salts or multi vitamins containing iron salts should be co administered
with caution. Iron salts can form chelates with levodopa and carbidopa and
consequently reduce the bioavailability of carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There were no significant differences between treated and control rats with respect to
mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135
mg/kg/day.Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were
given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia
was seen when compared to concurrent controls.
Mutagenesis
Mutagenicity studies have not been performed with either carbidopa or the combination of carbidopa and levodopa.
Fertility
Carbidopa had no effect on the mating performance, fertility, or survival of the young when administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a moderate decrease in body weight gain in males.
The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100 mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive performance, or the growth and survival of the young.
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies with LODOSYN in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. LODOSYN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by the concomitant administration of carbidopa.
Nursing Mothers
It is not known whether carbidopa is excreted in human milk. Because many drugs are excreted in human milk, and because of their potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established, and use of the drug in patients below the age of 18 is not recommended.
Geriatric Use
Clinical studies of LODOSYN did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease and other drug therapy.
|