Marinol

Generic Name: dronabinol

Dosage Form: capsule
Marinol®

(dronabinol) Capsules

Rx Only

CIII

Marinol Description

Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following empirical and structural formulas:

Dronabinol, the active ingredient in Marinol® (dronabinol) Capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Capsules for oral administration: Marinol Capsules is supplied as round, soft gelatin capsules containing either 2.5 mg, 5 mg, or 10 mg dronabinol. Each Marinol Capsule strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, and titanium dioxide; 5 mg capsule contains iron oxide red and iron oxide black, gelatin, glycerin, sesame oil, and titanium dioxide; 10 mg capsule contains iron oxide red and iron oxide yellow, gelatin, glycerin, sesame oil, and titanium dioxide.

Marinol - Clinical Pharmacology

Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol and other cannabinoids.

Pharmacodynamics

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing.

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient variability.

After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210 mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of Marinol Capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of Marinol Capsules has been sustained for up to five months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.

Pharmacokinetics

Absorption and Distribution: Marinol Capsules is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.

The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time.

The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day; BID) have been studied in healthy women and men.

Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Volunteers (n=34; 20-45 years) under Fasted Conditions

Mean (SD) PK Parameter Values
BID Dose	Cmax ng/mL	Median Tmax (range), hr	AUC(0-12) ng•hr/mL
2.5 mg	1.32 (0.62)	1.00 (0.50-4.00)	2.88 (1.57)
5 mg	2.96 (1.81)	2.50 (0.50-4.00)	6.16 (1.85)
10 mg	7.88 (4.54)	1.50 (0.50-3.50)	15.2 (5.52)

A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.

Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Elimination: Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of Marinol Capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Special Populations: The pharmacokinetic profile of Marinol Capsules has not been investigated in either pediatric or geriatric patients.

Clinical Trials

Appetite Stimulation: The appetite stimulant effect of Marinol Capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of Marinol Capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of Marinol Capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of Marinol Capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received Marinol and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received Marinol and 45 received placebo). A statistically significant difference between Marinol Capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with Marinol Capsules in an open-label study, in which there was a sustained improvement in appetite.

Antiemetic: Marinol Capsules treatment of chemotherapy-induced emesis was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic efficacy of Marinol Capsules was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin's and non-Hodgkin's lymphomas. Marinol Capsules dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the Marinol Capsules dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic benefit.

Marinol Capsules Dose: Response Frequency and Adverse Experiences*(N = 750 treatment courses)

*Nondysphoric events consisted of drowsiness, tachycardia, etc.
Marinol Capsules Dose	Response Frequency (%)			Adverse Events Frequency (%)
	Complete	Partial	Poor	None	Nondysphoric	Dysphoric
<7 mg/m2	36	32	32	23	65	12
>7 mg/m2	33	31	36	13	58	28

Combination antiemetic therapy with Marinol Capsules and a phenothiazine (prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents.

INDIVIDUALIZATION OF DOSAGES

The pharmacologic effects of Marinol Capsules are dose-related and subject to considerable interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of Marinol Capsules treatment.

Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day Marinol Capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:

1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high, dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued dosage.


2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms continue to be a problem, taking the single dose in the evening or at bedtime may reduce their severity.


3. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg. Although most patients respond to 2.5 mg twice daily, 10 mg twice daily has been tolerated in about half of the patients in appetite stimulation studies.

The pharmacologic effects of Marinol Capsules are reversible upon treatment cessation.

Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at the lowest recommended dosage and titrated to clinical response. Administration of Marinol Capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy as compared to either drug alone, without additional toxicity.

Pediatrics: Marinol Capsules is not recommended for AIDS-related anorexia in pediatric patients because it has not been studied in this population. The pediatric dosage for the treatment of chemotherapy-induced emesis is the same as in adults. Caution is recommended in prescribing Marinol Capsules for children because of the psychoactive effects.

Geriatrics: Caution is advised in prescribing Marinol Capsules in elderly patients because they may be more sensitive to the neurological, psychoactive and postural hypotensive effects of the drug. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (See PRECAUTIONS.)

Marinol Capsules should be used with caution when administered to elderly patients with dementia, who are at increased risk for falls as a result of their underlying disease state which may be exacerbated by the central nervous system effects of somnolence and dizziness associated with Marinol Capsules. These patients should be monitored closely and placed on fall precautions prior to initiating Marinol therapy. In antiemetic studies, no difference in efficacy was apparent in patients >55 years old.

Indications and Usage for Marinol

Marinol Capsules is indicated for the treatment of:

1. anorexia associated with weight loss in patients with AIDS; and


2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

Contraindications

Marinol Capsules is contraindicated in any patient who has a known sensitivity to Marinol Capsules or any of its ingredients. It contains cannabinoid and sesame oil and should never be used by patients allergic to these substances.

Warnings

Patients receiving treatment with Marinol Capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Precautions

General: The risk/benefit ratio of Marinol Capsules use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of Marinol Capsules.

Seizure and seizure-like activity have been reported in patients receiving Marinol Capsules during marketed use of the drug and in clinical trials. (See ADVERSE REACTIONS and OVERDOSAGE.) Marinol Capsules should be used with caution in patients with a history of seizure disorder because Marinol Capsules may lower the seizure threshold. A causal relationship between Marinol Capsules and these events has not been established. Marinol Capsules should be discontinued immediately in patients who develop seizures and medical attention should be sought immediately.

Marinol Capsules should be used with caution in patients with cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia. (See CLINICAL PHARMACOLOGY.)

Marinol Capsules should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence, because they may be more prone to abuse Marinol Capsules as well. Multiple substance abuse is common and marijuana, which contains the same active compound, is a frequently abused substance.

Marinol Capsules should be used with caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia because Marinol Capsules may exacerbate these illnesses.

Marinol Capsules should be used with caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects.

Marinol Capsules should be used with caution in elderly patients because they may be more sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug.(See INDIVIDUALIZATION OF DOSAGES.)

Marinol Capsules should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations.

Information for Patients: Patients receiving treatment with Marinol Capsules should be alerted to the potential for additive central nervous system depression if Marinol Capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates.

Patients receiving treatment with Marinol Capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Patients using Marinol Capsules should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under the supervision of a responsible adult during initial use of Marinol Capsules and following dosage adjustments.

Drug Interactions: In studies involving patients with AIDS and/or cancer, Marinol Capsules has been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of Marinol Capsules, cannabinoids may interact with other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving cannabinoids are summarized in the following table.

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in mice and rats have been conducted under the US National Toxicology Program (NTP). In the 2-year carcinogenicity study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and female mice but not at 250 or 500 mg/kg/day.

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 2 to 10 times MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. The significance of these animal findings in humans is not known.

Pregnancy: Pregnancy Category C. Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in rats at 74 to 295 mg/m2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20 times MRHD of 15 mg/m2/day in AIDS patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Use of Marinol Capsules is not recommended in nursing mothers since, in addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in human breast milk and is absorbed by the nursing baby.

Geriatric Use: Clinical studies of Marinol Capsules in AIDS and cancer patients did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported 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 falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of concomitant disease or other drug therapy.

Adverse Reactions

Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials conducted in the US and US territories involving 474 patients exposed to Marinol Capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of different durations were combined by considering the first occurrence of events during the first 28 days. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol and 68 receiving placebo.

A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by patients receiving Marinol Capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). (See Clinical Trials. )

The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving Marinol Capsules. About 25% of patients reported a minor CNS adverse event during the first 2 weeks and about 4% reported such an event each week for the next 6 weeks thereafter.

PROBABLY CAUSALLY RELATED: Incidence greater than 1%.

Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses).

*Incidence of events 3% to 10%

Body as a whole: Asthenia. Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush. Digestive: Abdominal pain*, nausea*, vomiting*. Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness*, euphoria*, (hallucination), paranoid reaction*, somnolence*, thinking abnormal*.

PROBABLY CAUSALLY RELATED: Incidence less than 1%.

Event rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317).

*Incidence of events 0.3% to 1%

Cardiovascular: Conjunctivitis*, hypotension*. Digestive: Diarrhea*, fecal incontinence. Musculoskeletal: Myalgias. Nervous system: Depression, nightmares, speech difficulties, tinnitus. Skin and Appendages: Flushing*. Special senses: Vision difficulties.

CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%.

The clinical significance of the association of these events with Marinol Capsules treatment is unknown, but they are reported as alerting information for the clinician.

Body as a whole: Chills, headache, malaise. Digestive: Anorexia, hepatic enzyme elevation. Respiratory: Cough, rhinitis, sinusitis. Skin and Appendages: Sweating.

Postmarketing Experience

Seizure and seizure-like activity have been reported in patients receiving Marinol Capsules during marketed use of the drug and in clinical trials. (See PRECAUTIONS and OVERDOSAGE.) Reports of fatigue have also been received. A causal relationship between Marinol Capsules and these events has not been established.

Drug Abuse and Dependence

Marinol Capsules is one of the psychoactive compounds present in cannabis, and is abusable and controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen after prolonged high dose administration.

Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgement, and perception. The etiology of these impairments is unknown, but may be associated with the complex process of addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological status have been associated with the administration of Marinol Capsules for therapeutic purposes.

In an open-label study in patients with AIDS who received Marinol Capsules for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in volunteers receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after discontinuation, these volunteers manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes”, sweating, rhinorrhea, loose stools, hiccoughs and anorexia.

These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

Overdosage

Signs and symptoms following MILD Marinol Capsules intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders.

The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/ 70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of Marinol Capsules.

Management: A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required.

Marinol Dosage and Administration

Appetite Stimulation: Initially, 2.5 mg Marinol Capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of Marinol Capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day Marinol Capsules, administered in divided oral doses. Caution should be exercised in escalating the dosage of Marinol Capsules because of the increased frequency of dose-related adverse experiences at higher dosages. (See PRECAUTIONS.)

Antiemetic: Marinol Capsules is best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose. (See PRECAUTIONS.)

Storage Conditions

Marinol Capsules should be packaged in a well-closed container and stored in a cool environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a refrigerator. Protect from freezing.

How is Marinol Supplied

Marinol Capsules (dronabinol solution in sesame oil in soft gelatin capsules)

2.5 mg white capsules (Identified UM).

NDC 0051-0021-21 (Bottle of 60 capsules).

5 mg dark brown capsules (Identified UM).

NDC 0051-0022-21 (Bottle of 60 capsules).

10 mg orange capsules (Identified UM).

NDC 0051-0023-21 (Bottle of 60 capsules).

Manufactured by:

Banner Pharmacaps, Inc.

High Point, NC 27265

For:

Abbott Laboratories

North Chicago, IL 60064, U.S.A.

500012 1E Rev Mar 2010

© 2010 Abbott Laboratories

PATIENT INFORMATION

Marinol® (dronabinol)

Capsules

2.5 mg, 5 mg, 10 mg

for use in the loss of appetite

associated with weight loss

in patients with AIDS.

IMPORTANT

YOUR DOCTOR HAS PRESCRIBED THIS DRUG FOR YOUR USE ONLY. DO NOT LET ANYONE ELSE USE IT.

KEEP THIS MEDICINE OUT OF THE REACH OF CHILDREN AND PETS. If a child puts a capsule in his or her mouth or swallows Marinol® Capsules, take the medicine away from the child and contact a poison control center immediately, or contact a doctor immediately.

Do not drive a car or operate machinery until you know how Marinol Capsules affects you. While taking Marinol Capsules, do not drink alcohol, smoke marijuana, or take other drugs that have an effect on the central nervous system (such as sedatives or hypnotics). Unless advised by your doctor, do not use Marinol Capsules if you are pregnant or nursing.

INTRODUCTION

This leaflet provides a summary of information about Marinol Capsules. Please read it and keep it with your medicines in case you need to look at it again. Ask your doctor, nurse, or pharmacist if you have any questions.

Marinol Capsules contains man-made dronabinol (THC). Dronabinol also occurs naturally, and has been extracted from Cannabis sativa L. (marijuana).

PRECAUTIONS

Be sure to tell your doctor if you:

• have or had heart disease


• have or had cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia


• have current or a history of drug abuse


• have current or a history of alcohol abuse


• have or had mental health problems (mania, depression, schizophrenia)


• have a history of seizure disorder and/or seizure-like activity


• have allergies to drugs


• are pregnant or nursing, or become pregnant

If you become pregnant while taking Marinol Capsules, stop using it until you have talked to your doctor.

Marinol Capsules should be used with caution in children because it has not been studied in children.

Marinol Capsules should be used with caution in elderly patients because they may be more sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug.

Marinol Capsules can dangerously interact with alcohol and with other drugs that have an effect on the central nervous system (such as Valium, Librium, Xanax, Seconal, Nembutal, or Phenobarbital).

Do not drive or operate machinery until you are sure how Marinol Capsules affects you and you are able to perform safely.

You may experience changes in mood or have other effects when first taking Marinol Capsules. Be sure that there is a responsible person nearby when you first take Marinol Capsules or when there is an adjustment in your dose.

Tell your doctor if you are taking any other prescription or nonprescription medicines.

Do not smoke marijuana while using Marinol Capsules. This can cause an overdose.

INFORMATION ABOUT USING Marinol CAPSULES

Introduction

Eating a nutritionally balanced diet is fundamental for all stages of life. For persons living with Human Immunodeficiency Virus (HIV); it’s especially important to ensure an adequate diet to maintain an ideal weight and good nutritional status. There is some indication that optimal nutrition can help maintain the integrity of the immune system, and an adequate diet will allow you to better withstand the diseases associated with an AIDS diagnosis.

Many conditions, frequently interrelated, may cause a loss of appetite. Chewing and swallowing may become difficult or painful, due to inflammation or sores in your mouth and throat.

You may experience intermittent diarrhea or overall physical discomfort associated with AIDS. Sometimes, shopping for food and preparing adequate meals may drain your energy and desire to eat. Mental depression also may result in a loss of your appetite, or you simply may grow increasingly frustrated with repeated eating problems.

A loss of appetite may occur at various times during illness associated with HIV infection. It often leads to the selection of an inadequate diet. Because a poor nutrient intake can result in weight loss and malnutrition, it’s important to learn to recognize and handle a temporary loss of your appetite.

Your doctor may prescribe an appetite stimulant such as Marinol Capsules. Marinol Capsules should be taken exactly as directed by your doctor, and indicated on the prescription label. You will most likely start therapy by taking one white capsule (2.5 mg) of Marinol Capsules twice daily, before lunch and supper. Your doctor may adjust your Marinol Capsules dosage if needed to maximize its effect or to decrease any side effects.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double your dose. Marinol Capsules must be swallowed whole to work effectively. Do not crush or chew the capsules.

It is important not to take sedatives, hypnotics, other mind altering substances, or alcohol, while taking Marinol Capsules without notifying your health care givers (physician, pharmacists and nurses). Do not drive or attempt other activities requiring full alertness while taking Marinol Capsules. Your doctor will advise when you may resume these activities.

Your doctor and pharmacist should be made aware of any other prescription medications or over-the-counter products you may be taking, as they could affect the way you respond to Marinol Capsules.

Remember to keep this and all other medication out of the reach of children.

Increasing your appetite is only the first step in improving your nutritional status. How, what, and when you eat are also very important.

How to Eat

The purpose of consuming an adequate diet, even at times when you don’t feel like eating, is to maintain an ideal weight and good nutritional status. Key to an adequate diet for HIV-infected individuals are foods dense in calories and nutrients. In other words, when you find it difficult to eat, make the most of what you do consume by selecting foods that provide many calories or nutrients in each mouthful.

Try some of the following ideas to boost your food intake. Keep in mind the foods you previously may have limited in your diet, especially those higher in fat, now can provide a significant source of calories. Enjoy an ice cream sundae frequently.

Cool or cold foods can dull pain from mouth and throat sores; popsicles may even numb your mouth prior to eating a larger meal. The cooler temperatures also diminish the aroma of unappetizing food.

Blend one cup of nonfat dry milk powder with one quart of whole milk. Refrigerate and use “double strength” milk for all traditional uses (puddings, cereal, shakes, soups).

Foods with a softer consistency, such as applesauce, may aid swallowing. Creamed sauces or gravies also moisten food to encourage swallowing.

Creating an appetizing meal involves more than just food. Try to eat in a pleasant atmosphere – sit in a comfortable chair, use a tablecloth and china, invite a friend to share your meal.

What to Eat

Planning ahead is one of the most effective ways to deal with a loss of appetite. Stock up on staple foods, particularly those high in calories and protein, so they’re available when you need them. Include favorite foods on your shopping list. Also consider these protein and nutrient dense foods:

• Nonfat dry milk powder


• Powdered breakfast drinks


• Peanut butter and jelly


• Pudding cups


• “Trail mix” (dried fruit, nuts, cereals)


• Creamed soups


• Canned (or frozen) fruit in heavy syrup


• Canned tuna, chicken or other sandwich spreads


• Boxed macaroni and cheese

In addition to staples, refrigerated and frozen foods contribute important nutrients to an adequate diet. Several key choices, high in protein and calories, are listed below:

• Yogurt


• Cheeses


• Cold cuts, beef and poultry


• Cottage cheese


• Ice cream and sherbet


• Popsicles or pudding pops


• Hard cooked eggs or pasteurized eggs*

*Raw or undercooked cracked eggs pose danger of Salmonella. The compromised immune function of persons with AIDS places them at greater than average risk from Salmonella infection.

Commercial food supplements are also available to boost your caloric and nutrient intake. Offered in a variety of flavors and textures, these products supply a concentrated source of calories and protein. You may want to ask your treatment provider for more information about supplements. You may also request a referral to a registered dietitian who can provide in

Lidocaine/Benzalkonium Cream

Pronunciation: LYE-doe-kane/BEN-zal-KOE-nee-um
Generic Name: Lidocaine/Benzalkonium
Brand Name: Examples include A + D Cracked Skin Relief and Dr. Scholl's Cracked Heel Relief

Lidocaine/Benzalkonium Cream is used for:

Relieving pain and itching caused by minor cuts, scrapes, and burns. It may also be used as first aid treatment to help prevent skin infection.

Lidocaine/Benzalkonium Cream is an antiseptic and anesthetic combination. It works by cleansing the wound. It also stops nerves from transmitting painful impulses to the brain.

Do NOT use Lidocaine/Benzalkonium Cream if:

• you are allergic to any ingredient in Lidocaine/Benzalkonium Cream or to similar medicines (eg, amide-type local anesthetics)


• you have signs of infection (eg, oozing, warmth, pain) or tissue damage in the affected area

Contact your doctor or health care provider right away if any of these apply to you.

Before using Lidocaine/Benzalkonium Cream:

Some medical conditions may interact with Lidocaine/Benzalkonium Cream. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to any anesthetic medicine


• if you have heart, liver, or kidney problems; diabetes; or poor circulation


• if the affected area is an animal bite, a burn, or a deep wound (eg, puncture wound), or if there is redness or swelling in the affected area

Some MEDICINES MAY INTERACT with Lidocaine/Benzalkonium Cream. Because little, if any, of Lidocaine/Benzalkonium Cream is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Lidocaine/Benzalkonium Cream may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Lidocaine/Benzalkonium Cream:

Use Lidocaine/Benzalkonium Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Wash your hands before and immediately after using Lidocaine/Benzalkonium Cream, unless your hands are part of the treated area.


• Wash and completely dry the affected area. Apply a thin layer of Lidocaine/Benzalkonium Cream to the affected area. Gently rub the medicine in until it is evenly distributed.


• If you miss a dose of Lidocaine/Benzalkonium Cream, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Ask your health care provider any questions you may have about how to use Lidocaine/Benzalkonium Cream.

Important safety information:

• Lidocaine/Benzalkonium Cream may cause harm if it is swallowed. If you may have taken it by mouth, contact your poison control center or emergency room right away.


• Lidocaine/Benzalkonium Cream is for external use only. Do not get it in your eyes or on the inside of your nose or mouth. If you get Lidocaine/Benzalkonium Cream in your eyes, rinse them immediately with cool water.


• Lidocaine/Benzalkonium Cream may cause a numbing effect at the application site. Do not scratch, rub, or expose the area to extreme hot or cold temperatures until the numbness is gone.


• Do not apply Lidocaine/Benzalkonium Cream over large areas of the body, to open wounds, or to blistered or infected skin without first checking with your doctor.


• Do not use more often than recommended or use for longer than 7 days without checking with your doctor.


• If you symptoms do not get better within 7 days or if they get worse, check with your doctor.


• Talk with your doctor before you use any other medicines or cleansers on your skin.


• Different brands of Lidocaine/Benzalkonium Cream may have different dosing instructions for CHILDREN. Follow the dosing instructions on the package labeling. If your doctor has given you instructions, follow those. If you are unsure of the dose to give to a child, check with your doctor or pharmacist.


• PREGNANCY and BREAST-FEEDING: It is not known if Lidocaine/Benzalkonium Cream can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Lidocaine/Benzalkonium Cream while you are pregnant. It is not known if Lidocaine/Benzalkonium Cream is found in breast milk after topical use. If you are or will be breast-feeding while you use Lidocaine/Benzalkonium Cream, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Lidocaine/Benzalkonium Cream:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Minor redness or swelling at the application site.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); excessive irritation; signs of infection in the affected area (eg, warmth, oozing, pain).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Lidocaine/Benzalkonium Cream may be harmful if swallowed.

Proper storage of Lidocaine/Benzalkonium Cream:

Store Lidocaine/Benzalkonium Cream at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Keep Lidocaine/Benzalkonium Cream out of the reach of children and away from pets.

General information:

• If you have any questions about Lidocaine/Benzalkonium Cream, please talk with your doctor, pharmacist, or other health care provider.


• Lidocaine/Benzalkonium Cream is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Discard unused medicine and packaging in the trash out of the reach of children and pets.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Lidocaine/Benzalkonium Cream. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Lidocaine/Benzalkonium resources

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• Lidocaine/Benzalkonium Drug Interactions
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• Bacterial Skin Infection

Kaletra Oral Solution

Generic Name: lopinavir and ritonavir

Dosage Form: Oral Solution

Kaletra Description

Kaletra (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV protease. As co-formulated in Kaletra, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

Lopinavir is chemically designated as [1S-[1R*,(R*), 3R*, 4R*]] - N - [4 - [[(2,6 - dimethylphenoxy)acetyl]amino] - 3 - hydroxy - 5 - phenyl - 1 - (phenylmethyl)pentyl]tetrahydro - alpha - (1 - methylethyl) - 2 - oxo - 1(2H) - pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is 628.80. Lopinavir has the following structural formula:

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Kaletra capsules are available for oral administration in a strength of 133.3 mg lopinavir and 33.3 mg ritonavir with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, propylene glycol, sorbitol special, titanium dioxide, and water.

Kaletra oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: Acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural& artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water.

Kaletra oral solution contains 42.4% alcohol (v/v).

Kaletra - Clinical Pharmacology

Microbiology

Mechanism of Action

Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

Antiviral Activity

The antiviral activity of lopinavir against laboratory HIV strains and clinical HIV isolates was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean 50% effective concentration (EC50) values of lopinavir against five different HIV-1 subtype B laboratory strains ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM) and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 subtype B clinical isolates (n = 6). In the presence of 50% human serum, the mean EC50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 µg/mL), representing a 7- to 11-fold attenuation. Combination antiviral drug activity studies with lopinavir in cell cultures demonstrated additive to antagonistic activity with nelfinavir and additive to synergistic activity with amprenavir, atazanavir, indinavir, saquinavir and tipranavir. The EC50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).

Resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.

The selection of resistance to Kaletra in antiretroviral treatment-naive patients has not yet been characterized. In a Phase III study of 653 antiretroviral treatment-naive patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to Kaletra was observed in 37 evaluable Kaletra-treated patients (0%). The selection of resistance to Kaletra in antiretroviral treatment-naive pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

Resistance to Kaletra has been noted to emerge in patients treated with other protease inhibitors prior to Kaletra therapy. In Phase II studies of 227 antiretroviral treatment-naive and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with Kaletra for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhibitor (indinavir, nelfinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, ritonavir, and saquinavir). All four of these patients had at least 4 mutations associated with protease inhibitor resistance immediately prior to Kaletra therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on Kaletra therapy. The assessment of these mutational patterns is under study.

Cross-resistance – Preclinical Studies

Varying degrees of cross-resistance have been observed among HIV protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during Kaletra therapy.

The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed >4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed <4-fold reduced susceptibility to lopinavir. Isolates with >4-fold reduced susceptibility to indinavir (n = 16) and ritonavir (n = 3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following paragraph.

Clinical Studies – Antiviral Activity of Kaletra in Patients with Previous Protease Inhibitor Therapies

The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to Kaletra therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

Virologic response to Kaletra has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 1 shows the 48-week virologic response (HIV RNA <400 copies/mL) according to the number of the above protease inhibitor resistance mutations at baseline in studies 888 and 765 (see INDICATIONS AND USAGE) and study 957 (see below).

Table 1. Virologic Response (HIV RNA <400 copies/mL) at Week 48 by Baseline Kaletra Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to Kaletra1

Number of protease inhibitor mutations at baseline1	Study 888 (Single protease inhibitor-experienced2, NNRTI-naïve) n=130	Study 765 (Single protease inhibitor-experienced 3, NNRTI-naïve) n=56	Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naïve) n=50
1   Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 2   43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 3   41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir. 4   86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.
0-2	76/103 (74%)	34/45 (76%)	19/20 (95%)
3-5	13/26 (50%)	8/11 (73%)	18/26 (69%)
6 or more	0/1 (0%)	n/a	1/4 (25%)

Virologic response to Kaletra therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of Kaletra in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC50 value. Fifty-five percent (31/56) of these baseline isolates displayed > 4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 2.

Table 2. HIV-RNA Response at Week 48 by Baseline Lopinavir Susceptibility1

Lopinavir susceptibility2 at baseline	HIV RNA < 400 copies/mL (%)	HIV RNA < 50 copies/mL (%)
1   Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2   Fold change in susceptibility from wild type.
<10 fold	25/27 (93%)	22/27 (81%)
>10 and <40 fold	11/15 (73%)	9/15 (60%)
≥40 fold	2/8 (25%)	2/8 (25%)

Pharmacokinetics

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice-daily yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice-daily. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir.

Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after Kaletra 400/100 mg twice-daily with food for 3 weeks from a pharmacokinetic study in HIV-infected adult subjects (n = 19).

Figure 1. Mean Steady-state Plasma Concentrations with 95% Confidence Intervals (CI) for HIV-Infected Adult Subjects (N = 19)

Absorption

In a pharmacokinetic study in HIV-positive subjects (n = 19), multiple dosing with 400/100 mg Kaletra twice-daily with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.8 ± 3.7 µg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 µg/mL and minimum concentration within a dosing interval was 5.5 ± 2.7 µg/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 µg• h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of Kaletra co-formulated capsules and liquid. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the Kaletra liquid relative to the capsule formulation.

Effects of Food on Oral Absorption

Administration of a single 400/100 mg dose of Kaletra capsules with a moderate fat meal (500-682 kcal, 23 to 25% calories from fat) was associated with a mean increase of 48 and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and Cmax were 80 and 54%, respectively. Relative to fasting, administration of Kaletra with a high fat meal (872 kcal, 56% from fat) increased lopinavir AUC and Cmax by 97 and 43%, respectively, for capsules, and 130 and 56%, respectively, for oral solution. To enhance bioavailability and minimize pharmacokinetic variability Kaletra should be taken with food.

Distribution

At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice-daily, and is similar between healthy volunteers and HIV-positive patients.

Metabolism

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.

Elimination

Following a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and feces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L/hr (mean ± SD, n = 19).

Once Daily Dosing

The pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg Kaletra once-daily for 4 weeks with food (n = 24) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 µg/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 µg/mL and minimum concentration within a dosing interval was 1.7 ± 1.6 µg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 ± 61.4 µg• h/mL.

Special Populations

Gender, Race and Age

Lopinavir pharmacokinetics have not been studied in elderly patients. No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified.

Pediatric Patients

The pharmacokinetics of Kaletra 300/75 mg/m2 twice-daily and 230/57.5 mg/m2 twice-daily have been studied in a total of 53 pediatric patients, ranging in age from 6 months to 12 years. The 230/57.5 mg/m2 twice-daily regimen without nevirapine and the 300/75 mg/m2 twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen (without nevirapine). Kaletra once-daily has not been evaluated in pediatric patients.

The mean steady-state lopinavir AUC, Cmax, and Cmin were 72.6 ± 31.1 µg•h/mL, 8.2 ± 2.9 and 3.4± 2.1 µg/mL, respectively after Kaletra 230/57.5 mg/m2 twice-daily without nevirapine (n = 12), and were 85.8 ± 36.9 µg• h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 µg/mL, respectively, after 300/75 mg/m2 twice-daily with nevirapine (n = 12). The nevirapine regimen was 7 mg/kg twice-daily (6 months to 8 years) or 4 mg/kg twice-daily (> 8 years).

Renal Insufficiency

Lopinavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic Impairment

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of Kaletra 400/100 mg twice-daily to HIV and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Caution should be exercised when administering Kaletra to subjects with hepatic impairment. Kaletra has not been studied in patients with severe hepatic impairment (see PRECAUTIONS ).

Drug-drug Interactions

See also CONTRAINDICATIONS , WARNINGS and PRECAUTIONS– Drug Interactions.

Kaletra is an inhibitor of the P450 isoform CYP3A in vitro. Co-administration of Kaletra and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS).

Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.

Kaletra is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, co-administration of Kaletra and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drug interaction studies were performed with Kaletra and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of Kaletra on the AUC, Cmax and Cmin are summarized in Table 3 (effect of other drugs on lopinavir) and Table 4 (effect of Kaletra on other drugs). The effects of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are decreased) unless otherwise indicated in the table footnotes. For information regarding clinical recommendations, see Table 11 in PRECAUTIONS .

Table 3. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug (See PRECAUTIONS – Table 11 for Recommended Alterations in Dose or Regimen)

Co-administered Drug	Dose of Co-administered Drug (mg)	Dose of Kaletra (mg)	n	Ratio (in combination with Co-administered drug-/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Cmax	AUC		Cmin
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1   The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2   Data extracted from the fosamprenavir package insert. 3  Study conducted in HIV-positive adult subjects. 4   Study conducted in HIV-positive pediatric subjects ranging in age from 6 months to 12 years. 5   Titrated to 800/200 BID as 533/133 BID x 1 d, 667/167 BID x 1 d, then 800/200 BID x 7 d, compared to 400/100 BID x 10 days alone. 6   Titrated to 400/400 BID as 400/200 BID x 1 d, 400/300 BID x 1 d, then 400/400 BID x 7 d, compared to 400/100 BID x 10 days alone. 7  Data extracted from the tenofovir package insert. 8  Intensive PK analysis. 9   Drug levels obtained at 8-16 hrs post-dose. *  Parallel group design; n for Kaletra + co-administered drug, n for Kaletra alone. †   NC = No change.
Amprenavir	750 BID, 10 d	400/100 BID, 21 d	12	0.72 (0.65, 0.79)	0.62 (0.56, 0.70)		0.43 (0.34, 0.56)
Atorvastatin	20 QD, 4 d	400/100 BID, 14 d	12	0.90 (0.78, 1.06)	0.90 (0.79, 1.02)		0.92 (0.78, 1.10)
Efavirenz1	600 QHS, 9 d	400/100 BID, 9 d	11, 7*	0.97 (0.78, 1.22)	0.81 (0.64, 1.03)		0.61 (0.38, 0.97)
Fosamprenavir2	700 BID plus ritonavir 100 BID, 14 d	400/100 BID, 14 d	18	1.30 (0.85, 1.47)	1.37 (0.80, 1.55)		1.52 (0.72, 1.82)
Ketoconazole	200 single dose	400/100 BID, 16 d	12	0.89 (0.80, 0.99)	0.87 (0.75, 1.00)		0.75 (0.55, 1.00)
Nelfinavir	1000 BID, 10 d	400/100 BID, 21 d	13	0.79 (0.70, 0.89)	0.73 (0.63, 0.85)		0.62 (0.49, 0.78)
Nevirapine	200 BID, steady-state (> 1 yr)3	400/100 BID, steady-state	22, 19*	0.81 (0.62, 1.05)	0.73 (0.53, 0.98)		0.49 (0.28, 0.74)
	7 mg/kg or 4 mg/kg QD, 2 wk; BID 1 wk4	(> 1 yr) 300/75 mg/m2 BID, 3 wk	12, 15*	0.86 (0.64, 1.16)	0.78 (0.56, 1.09)		0.45 (0.25, 0.81)
Omeprazole	40 QD, 5 d	400/100 tablet BID, 10 d	12	1.08 (0.99, 1.17)	1.07 (0.99, 1.15)		1.03 (0.90, 1.18)
	40 QD, 5 d	800/200 tablet QD, 10 d	12	0.94 (0.88, 1.00)	0.92 (0.86, 0.99)		0.71 (0.57, 0.89)
Pravastatin	20 QD, 4 d	400/100 BID, 14 d	12	0.98 (0.89, 1.08)	0.95 (0.85, 1.05)		0.88 (0.77, 1.02)
Rifabutin	150 QD, 10 d	400/100 BID, 20 d	14	1.08 (0.97, 1.19)	1.17 (1.04, 1.31)		1.20 (0.96, 1.65)
Ranitidine	150 single dose	400/100 tablet BID, 10 d	12	0.99 (0.95, 1.03)	0.97 (0.93, 1.01)		0.90 (0.85, 0.95)
	150 single dose	800/200 tablet QD, 10 d	10	0.97 (0.95, 1.00)	0.95 (0.91, 0.99)		0.82 (0.74, 0.91)
Rifampin	600 QD, 10 d	400/100 BID, 20 d	22	0.45 (0.40, 0.51)	0.25 (0.21, 0.29)		0.01 (0.01, 0.02)
	600 QD, 14 d	800/200 BID, 9 d5	10	1.02 (0.85, 1.23)	0.84 (0.64, 1.10)		0.43 (0.19, 0.96)
	600 QD, 14 d	400/400 BID, 9 d6	9	0.93 (0.81, 1.07)	0.98 (0.81, 1.17)		1.03 (0.68, 1.56)
					Co-administration of Kaletra and rifampin is not recommended. (See PRECAUTIONS – Table 10 and Table 11)
Ritonavir3	100 BID, 3-4 wk	400/100 BID, 3-4 wk	8, 21*	1.28 (0.94, 1.76)	1.46 (1.04, 2.06)	2.16 (1.29, 3.62)
Tenofovir7	300 mg QD, 14 d	400/100 BID, 14 d	24	NC†	NC†	NC†
Tipranavir/ritonavir3	500/200 mg BID (28 doses)	400/100 capsule BID (27 doses)	21 69	0.53 (0.40, 0.69)8	0.45 (0.32, 0.63)8	0.30 (0.17, 0.51)8 0.48 (0.40, 0.58)9

Table 4. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Kaletra (See PRECAUTIONS – Table 11 for Recommended Alterations in Dose or Regimen)

Co-administered Drug	Dose of Co-administered Drug (mg)	Dose of Kaletra (mg)	n	Ratio (in combination with Kaletra/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Cmax	AUC	Cmin
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1  Ratio of parameters for amprenavir, indinavir, nelfinavir, and saquinavir are not normalized for dose. 2  Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism. 3   Data extracted from the fosamprenavir package insert. 4  Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite. 5   Data extracted from the rosuvastatin package insert and results presented at the 2007 Conference on Retroviruses and Opportunistic Infection (Hoody, et al, abstract L-107, poster #564). 6   Data extracted from the tenofovir package insert. *   Parallel group design; n for Kaletra + co-administered drug, n for co-administered drug alone. N/A = Not available. †   NC = No change.
Amprenavir1	750 BID, 10 d combo vs. 1200 BID, 14 d alone	400/100 BID, 21 d	11	1.12 (0.91, 1.39)	1.72 (1.41, 2.09)	4.57 (3.51, 5.95)
Atorvastatin	20 QD, 4 d	400/100 BID, 14 d	12	4.67 (3.35, 6.51)	5.88 (4.69, 7.37)	2.28 (1.91, 2.71)
Desipramine2	100 single dose	400/100 BID, 10 d	15	0.91 (0.84, 0.97)	1.05 (0.96, 1.16)	N/A
Efavirenz	600 QHS, 9 d	400/100 BID, 9 d	11, 12*	0.91 (0.72, 1.15)	0.84 (0.62, 1.15)	0.84 (0.58, 1.20)
Ethinyl Estradiol	35 µg QD, 21 d (Ortho Novum®)	400/100 BID, 14 d	12	0.59 (0.52, 0.66)	0.58 (0.54, 0.62)	0.42 (0.36, 0.49)
Fosamprenavir3	700 BID plus ritonavir 100 BID, 14 d	400/100 BID, 14 d	18	0.42 (0.30, 0.58)	0.37 (0.28, 0.49)	0.35 (0.27, 0.46)
Indinavir1	600 BID, 10 d combo nonfasting vs. 800 TID, 5 d alone fasting	400/100 BID, 15 d	13	0.71 (0.63, 0.81)	0.91 (0.75, 1.10)	3.47 (2.60, 4.64)
Ketoconazole	200 single dose	400/100 BID, 16 d	12	1.13 (0.91, 1.40)	3.04 (2.44, 3.79)	N/A
Methadone	5 single dose	400/100 BID, 10 d	11	0.55 (0.48, 0.64)	0.47 (0.42, 0.53)	N/A
Nelfinavir1	1000 BID, 10 d combo vs. 1250 BID, 14 d alone	400/100 BID, 21 d	13	0.93 (0.82, 1.05)	1.07 (0.95, 1.19)	1.86 (1.57, 2.22)
M8 metabolite				2.36 (1.91, 2.91)	3.46 (2.78, 4.31)	7.49 (5.85, 9.58)
Nevirapine	200 QD, 14 d; BID, 6 d	400/100 BID, 20 d	5, 6*	1.05 (0.72, 1.52)	1.08 (0.72, 1.64)	1.15 (0.71, 1.86)
Norethindrone	1 QD, 21 d (Ortho Novum®)	400/100 BID, 14 d	12	0.84 (0.75, 0.94)	0.83 (0.73, 0.94)	0.68 (0.54, 0.85)
Pravastatin	20 QD, 4 d	400/100 BID, 14 d	12	1.26 (0.87, 1.83)	1.33 (0.91, 1.94)	N/A
Rifabutin	150 QD, 10 d; combo vs. 300 QD, 10 d; alone	400/100 BID, 10 d	12	2.12 (1.89, 2.38)	3.03 (2.79, 3.30)	4.90 (3.18, 5.76)
25-O-desacetyl rifabutin				23.6 (13.7, 25.3)	47.5 (29.3, 51.8)	94.9 (74.0, 122)
Rifabutin + 25-O-desacetyl rifabutin4				3.46 (3.07, 3.91)	5.73 (5.08, 6.46)	9.53 (7.56, 12.01)
Rosuvastatin5	20 mg QD, 7 d	400/100 tablet BID, 7 d	15	4.66 (3.4, 6.4)	2.08 (1.66, 2.6)	1.04 (0.9, 1.2)
Saquinavir1	800 BID, 10 d combo vs. 1200 TID, 5 d alone,	400/100 BID, 15 d	14	6.34 (5.32, 7.55)	9.62 (8.05, 11.49)	16.74 (13.73, 20.42)
	1200 BID, 5 d combo vs. 1200 TID, 5 d alone	400/100 BID, 20 d	10	6.44 (5.59, 7.41)	9.91 (8.28, 11.86)	16.54 (10.91, 25.08)
Tenofovir6	300 mg QD, 14 d	400/100 BID, 14 d	24	NC†	1.32 (1.26, 1.38)	1.51 (1.32, 1.66)

Indications and Usage for Kaletra

Kaletra is indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

Once-daily administration of Kaletra is not recommended in therapy-experienced patients.

When initiating treatment with Kaletra in therapy-naïve patients, it should be noted that the incidence of diarrhea was greater for Kaletra once-daily compared to Kaletra twice-daily in Study 418 (57% vs. 35% - events of all grades and probably or possibly related to drug; 16% vs. 5% - events of at least moderate severity and probably or possibly related to drug) (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION ).

Description of Clinical Studies

Patients Without Prior Antiretroviral Therapy

Study 863: Kaletra twice-daily + stavudine + lamivudine compared to nelfinavir three-times-daily + stavudine + lamivudine

Study 863 is an ongoing, randomized, double-blind, multicenter trial comparing treatment with Kaletra (400/100 mg twice-daily) plus stavudine and lamivudine versus nelfinavir (750 mg three-times-daily) plus stavudine and lamivudine in 653 antiretroviral treatment-naïve patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4 cell count was 259 cells/mm3 (range: 2 to 949 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 2.6 to 6.8 log10 copies/mL).

Treatment response and outcomes of randomized treatment are presented in Table 5.

Table 5. Outcomes of Randomized Treatment Through Week 48 (Study 863)

Outcome	Kaletra+d4T+3TC (N = 326)	Nelfinavir+d4T+3TC (N = 327)
1   Patients achieved and maintained confirmed HIV RNA < 400 copies/mL through Week 48. 2   Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48. 3   Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the Kaletra arm and 24% in the nelfinavir arm.
Responder1	75%	62%
Virologic failure2     Rebound    Never suppressed through Week 48	9% 7% 2%	25% 15% 9%
Death	2%	1%
Discontinued due to adverse event	4%	4%
Discontinued for other reasons3	10%	8%

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the Kaletra arm compared to the nelfinavir arm with HIV RNA < 400 copies/mL (75% vs. 62%, respectively) and HIV RNA < 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table 6.

Table 6. Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863)

Baseline Viral Load (HIV-1 RNA copies/mL)	Kaletra +d4T+3TC			Nelfinavir +d4T+3TC
	< 400 copies/mL 1	< 50 copies/mL 2	n	< 400 copies/mL 1	< 50 copies/mL 2	n
1   Patients achieved and maintained confirmed HIV RNA < 400 copies/mL through Week 48. 2   Patients achieved HIV RNA < 50 copies/mL at Week 48.
< 30,000	74%	71%	82	79%	72%	87
≥ 30,000 to < 100,000	81%	73%	79	67%	54%	79
≥ 100,000 to < 250,000	75%	64%	83	60%	47%	72
≥ 250,000	72%	60%	82	44%	33%	89

Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 207 cells/mm3 for the Kaletra arm and 195 cells/mm3 for the nelfinavir arm.

Study 418: Kaletra once-daily + tenofovir DF + emtricitabine compared to Kaletra twice-daily + tenofovir DF + emtricitabine

Study 418 is an ongoing, randomized, open-label, multicenter trial comparing treatment with Kaletra 800/200 mg once-daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 190 antiretroviral treatment-naïve patients. Patients had a mean age of 39 years (range: 19 to 75), 54% were Caucasian, and 78% were male. Mean baseline CD4 cell count was 260 cells/mm3 (range: 3 to 1006 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range: 2.6 to 6.4 log10 copies/mL).

Treatment response and outcomes of randomized treatment are presented in Table 7.

Table 7. Outcomes of Randomized Treatment Through Week 48 (Study 418)

Outcome	Kaletra QD + TDF + FTC (n = 115)	Kaletra BID + TDF + FTC (n = 75)
1   Patients achieved and maintained confirmed HIV RNA < 50 copies/mL through Week 48. 2   Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48. 3   Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other reasons.
Responder1	71%	65%
Virologic failure2 Rebound Never suppressed through Week 48	10% 6% 3%	9% 5% 4%

Cetacaine Topical Anesthetic

benzocaine, butamben and tetracaine hydrochloride

Dosage Form: topical liquid
Cetacaine Topical Anesthetic

Action

The onset of Cetacaine-produced anesthesia is rapid (approximately

30 seconds) and the duration of anesthesia is typically 30-60 minutes,

when used as directed. This effect is due to the rapid onset, but short

duration of action of Benzocaine coupled with the slow onset, but extended

duration of Tetracaine HCI and bridged by the intermediate action

of Butamben.


It is believed that all of these agents act by reversibly blocking nerve

conduction. Speed and duration of action is determined by the ability

of the agent to be absorbed by the mucous membrane and nerve

sheath and then to diffuse out, and ultimately be metabolized (primarily

by plasma cholinesterases) to inert metabolites which are excreted in

the urine.

Indications

Cetacaine is a topical anesthetic indicated for the production of anesthesia

of all accessible mucous membrane except the eyes. Cetacaine

Spray is indicated for use to control pain or gagging.

Cetacaine in all forms is indicated to control pain and for use for surgical

or endoscopic or other procedures in the ear, nose, mouth, pharynx,

larynx, trachea, bronchi, and esophagus. It may also be used for

vaginal or rectal procedures when feasible.

Dosage and Administration

Cetacaine Liquid

Instructions for Subgingival Delivery:

1. Remove the shipping cap, discard and replace with Luer-lock dispensing cap.  Note:  Once dispensing cap is in place, it should not be removed.


2. Remove the small cap from the Luer-lock port.  Retain for replacement after use.


3. Lock a 1.2 mL Luer-lock syringe into the port.


4. Invert the bottle and slowly draw liquid (0.4 mL maximum) into syringe.  If air is drawn into syringe, push the liquid back into the bottle and slowly redraw liquid into syringe.


5. Holding bottle upright, remove the syringe from the port and replace the small port cap.


6. Attach a 27 ga Vista-Probe Tip to the syringe.  The tip may be bent to improve access.  Do not bend tip more than once in the same location.  If more than a 45 degree angle is desired, bend in two locations.  Bending at the hub may increase the risk of breakage.


7. Apply Cetacaine Liquid drop-wise to accessible mucous membrane (such as the buccal and lingual sulcus) by slowly depressing the syringe plunger.


8. Wait 1 minute for maximum anesthesia before beginning procedure.  The duration of anesthesia is typically 3--60 minutes, when used as directed.  Discard syringe and tip after use.

Alternate Method:  Instructions for Topical Delivery

                          using a Microbrush

1. Remove the shipping cap, discard and replace with Luer-lock dispensing cap.  Note:  Once dispensing cap is in place, it should not be removed. 
   


2. Remove the small cap from the Luer-lock port.  Retain for replacement after use.


3. Luer-lock port allows single dip of appropriate brush or applicator.


4. Applhy Cetacaine Liquid to accessible mucous membrane using the microbrush.


5. Wait 1 minute for maximum anesthesia before beginning procedure.  The duration of anesthesia is typically 30-60 minutes, when used as directed.  Discard microbrush after use.

Cetacaine Spray should be applied for approximately one second or

less for normal anesthesia. Only a limited quantity of Cetacaine is

required for anesthesia. Spray in excess of two seconds is

contraindicated. Average expulsion rate of residue from spray, at normal

temperatures, is 200 mg per second.

To apply, insert the Jetco cannula (J-4) firmly onto the protruding plastic

stem on the bottle and press the cannula forward to actuate the spray

valve. The cannula may be removed and reinserted as many times as

required for cleaning, or sterilization, and is autoclavable.

Cetacaine Liquid Apply 200 mg (approximately 6 – 7 drops or 0.2 cc)

with a cotton applicator or directly to tissue. Do not hold the cotton

applicator in position for extended periods of time, since local reactions

to benzoate topical anesthetics are related to the length of time

of application. Liquid in excess of 400 mg (approx. 12 – 14 drops or

0.4 cc) is contraindicated.

*See Cetacaine Liquid Kit instructions for additional directions for application

by Luer-lock syringe and applicator tip.

Cetacaine Gel Apply 200 mg of gel (a bead approximately 0.5 inch

(13 mm) in length and 3/16 inch (5 mm) in diameter) and spread thinly

and evenly over the application area. Gel in excess of 400 mg (a bead

approximately 1 inch (26 mm) in length and 3/16 inch (5 mm) in diameter)

is contraindicated.

An appropriate pediatric dosage has not been established for Cetacaine

Spray, Liquid or Gel.

Dosages should be reduced in the debilitated elderly, acutely ill, and

very young patients.

Tissue need not be dried prior to application of Cetacaine. Cetacaine

should be applied directly to the site where pain control is required.

Anesthesia is produced within one minute with an approximate

duration of thirty minutes. Each 200 mg dose of Cetacaine (Spray

residue, Liquid or Gel) contains 28 mg of benzocaine, 4 mg of butamben

and 4 mg of tetracaine HCl.

Adverse Reactions

Hypersensitivity Reactions: Unpredictable adverse reactions (i.e. hypersensitivity,

including anaphylaxis) are extremely rare.

Localized allergic reactions may occur after prolonged or repeated use

of any aminobenzoate anesthetic. The most common adverse reaction

caused by local anesthetics is contact dermatitis characterized by erythema

and pruritus that may progress to vesiculation and oozing. This

occurs most commonly in patients following prolonged self-medication,

which is contraindicated. If rash, urticaria, edema, or other manifestations

of allergy develop during use, the drug should be discontinued. To minimize

the possibility of a serious allergic reaction, Cetacaine preparations should not

be applied for prolonged periods except under continual supervision. Dehydration

of the epithelium or an escharotic effect may also result from prolonged contact.

Precaution: On rare occasions, methemoglobinemia has been reported

in connection with the use of benzocaine-containing products.

Care should be used not to exceed the maximum recommended

dosage (see Dosage and Administration). If a patient becomes cyanotic, treat appropriately

to counteract (such as with methylene blue, if medically indicated).

Use in Pregnancy

Safe use of Cetacaine has not been established

with respect to possible adverse effects upon fetal development.

Therefore, Cetacaine should not be used during early pregnancy, unless

in the judgment of a physician, the potential benefits outweigh

the unknown hazards. Routine precaution for the use of any topical

anesthetic should be observed when Cetacaine is used.

Cetacaine is not suitable and should never be used for injection. Do

not use on the eyes. To avoid excessive systemic absorption, Cetacaine

should not be applied to large areas of denuded or inflamed tissue.

Cetacaine should not be administered to patients who are

hypersensitive to any of its ingredients or to patients known to have

cholinesterase deficiencies. Tolerance may vary with the status of the

patient.

Cetacaine should not be used under dentures or cotton rolls, as retention

of the active ingredients under a denture or cotton roll could possibly

cause an escharotic effect. Routine precaution for the use of any

topical anesthetic should be observed when using Cetacaine.

How Supplied


• Cetacaine Liquid Kit (NDC 10223-0202-3, Item # 0210 ) which includes

   one 14 g bottle of Cetacaine Liquid with Leur-lock dispenser

   cap, 20 syringes and 20 applicator tips.

• Cetacaine Liquid, 14 g bottle (NDC 10223-0202-2, Item # 0203)

• Cetacaine Liquid, 30 g bottle (NDC 10223-0202-4, Item # 0211)


Available From Your Dealer:


• 1.2 mL Luer-lock syringes

• Tips, 27 ga

• Microbrushes



Cetacaine Liquid is not suitable for injection.  Do not use on the eyes.

RX Only.

Cetacaine Topical Anesthetic   benzocaine, butamben and tetracaine hydrochloride topical aerosol  liquid

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 10223-0202 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Benzocaine (Benzocaine) Benzocaine 0.028 g  in 0.2 g Butamben (Butamben) Butamben 0.004 g  in 0.2 g Tetracaine hydrochloride (Tetracaine) Tetracaine hydrochloride 0.004 g  in 0.2 g

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor BANANA (Artificial Banana Flavor) Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 10223-0202-2 14 g In 1 BOTTLE, GLASS None 2 10223-0202-4 30 g In 1 BOTTLE, GLASS None 3 10223-0202-3 14 g In 1 KIT None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		01/01/1958

Labeler - Cetylite Industries Inc. (001283704)

Registrant - Cetylite Industries Inc. (001283704)

Establishment
Name	Address	ID/FEI	Operations
Cetylite Industries Inc.		001283704	manufacture

Revised: 03/2011Cetylite Industries Inc.

More Cetacaine Topical Anesthetic resources

• Cetacaine Topical Anesthetic Side Effects (in more detail)
• Cetacaine Topical Anesthetic Use in Pregnancy & Breastfeeding
• Cetacaine Topical Anesthetic Support Group
• 0 Reviews · Be the first to review/rate this drug

Cafergot Suppositories

Cafergot
Suppositories 2 mg

ergotamine tartrate and caffeine

Read all of this leaflet carefully before you start using this medicine

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet please tell your doctor or pharmacist.

The information in this leaflet has been divided into the following sections:

• 
  1. What Cafergot Suppositories are and what they are used for
  


• 
  2. Check before you use Cafergot Suppositories
  


• 
  3. How to use Cafergot Suppositories
  


• 
  4. Possible side effects
  


• 
  5. How to store Cafergot Suppositories
  


• 
  6. Further information
  

What Cafergot Suppositories are and what they are used for

Cafergot Suppositories belong to a group of medicines called antimigraine drugs.

Cafergot Suppositories are for insertion into the back passage (rectum).

Cafergot Suppositories are used to treat migraines which have not responded to simple painkillers. They are used at the first sign of a migraine attack to relieve the symptoms and to stop the attack getting worse.

Do not use Cafergot Suppositories to prevent migraine attacks.

Check before you use Cafergot Suppositories

Do not use Cafergot Suppositories if you:

• are allergic (hypersensitive) to ergotamine tartrate, caffeine or any of the ingredients of Cafergot Suppositories (see section 6 Further information)


• have poor blood circulation to your arms and legs


• suffer from heart problems


• have high blood pressure which has not been controlled by treatment


• are suffering from a severe infection (septic shock)


• suffer from kidney problems


• suffer from liver disease


• suffer from a condition known as giant cell arteritis or temporal arteritis (the symptoms of which can include severe headache, a tender scalp and problems with your vision)


• suffer from a specific type of migraine called a basilar migraine (symptoms of which include giddiness, double vision, unsteadiness, fainting or loss of consciousness) or a hemiplegic migraine (symptoms of which include temporary paralysis down one side of the body, hearing impairment, numbness around the mouth leading to trouble speaking or swallowing)


• are pregnant or breast-feeding


• are taking a certain type of antibiotics (called macrolides) for example, erythromycin, clarithromycin, azithromycin


• are taking medicines to treat HIV or AIDS (called HIV-protease or reverse-transcriptase inhibitors) for example, amprenavir, indinavir


• are taking certain types of antifungals (called azole antifungals) for example, ketoconazole, miconazole


• are taking other anti-migraine drugs (including ergot alkaloids or drugs that end in ‘triptan’ such as sumatriptan, almotriptan, rizatriptan).

Do not give Cafergot Suppositories to children under 12 years old.

If any of the above applies to you, or if you are not sure, speak to your doctor or pharmacist before you use Cafergot Suppositories.

Take special care with Cafergot Suppositories

Before you use Cafergot Suppositories tell your doctor if:

• you have taken a triptan (such as almotriptan, rizatriptan, sumatriptan or zolmitriptan) in the last 6 hours


• you are a smoker.

If any of the above applies to you, or if you are not sure, speak to your doctor or pharmacist before you use Cafergot Suppositories.

If you attend hospital, or are about to have an operation or medical procedure tell the medical staff that you use Cafergot Suppositories.

Taking other medicines

Tell your doctor or pharmacist if you are taking or have recently taken any of the following medicines as they may interfere with Cafergot Suppositories:

• 
  
  antibiotics
  - used to treat bacterial infections such as macrolides (for example, erythromycin, azithromycin, clarithromycin, spiramycin, telithromycin), quinupristin, dalfopristin, tetracycline


• 
  antifungals
  - used to treat fungal infections such as, ketoconazole, miconazole, itraconazole, posaconazole, voriconazole


• 
  antivirals
  - used to treat HIV infection such as amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, atazanavir, efavirenz


• 
  5HT₁ agonists (triptans)
  - used to treat migraines such as almotriptan, rizatriptan, sumatriptan, zolmitriptan, eletriptan, frovatriptan


• 
  cimetidine
  - used to treat stomach ulcers and heartburn
  


• treatments for low blood pressure for example ephedrine hydrochloride, metaraminol


• beta-blockers
  - used to treat heart disease, angina and other heart disorders such as propranolol, oxprenolol, atenolol


• 
  nicotine
  - for example from smoking or nicotine replacement therapy (nicotine patches or gum)
  


• 
  certain general anaesthetics
  
  - for example halothane
  


• 
  certain antidepressants
  - for example reboxetine.
  
  
  

Please tell your doctor or pharmacist if you are taking or have recently taken/used any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Do not use Cafergot Suppositories if you are pregnant or breast-feeding.

Cafergot Suppositories can be passed into breast milk and may cause vomiting, diarrhoea, changes in blood pressure and a weak heartbeat in your baby. If you become pregnant whilst using Cafergot Suppositories tell your doctor immediately.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Cafergot Suppositories may make you dizzy or anxious. If you are affected do not drive or operate machinery until these effects have worn off.

How to use Cafergot Suppositories

Always use Cafergot Suppositories exactly as your doctor has told you to. You should check with your doctor or pharmacist if you are not sure.

Adults and the Elderly

Cafergot Suppositories should be inserted into the back passage (rectum). The usual dosage is one suppository used at the first sign of a migraine attack. Your doctor may increase your dose to two suppositories in 24 hours, however it is important to use the lowest dose which is effective.

Keep a record of how many suppositories you use.

It is important that you:

• do not use more than 2 Cafergot Suppositories in 24 hours


• do not use Cafergot Suppositories every day to prevent migraines


• do not use Cafergot Suppositories if you have already used a course of treatment within the last 4 days


• do not use more than 4 Cafergot Suppositories in a week

If you are not getting relief from your migraine do not use more suppositories, tell your doctor.

Children

Do not give Cafergot Suppositories to children under 12 years old.

What to do if you use more Cafergot Suppositories than you should

If you accidentally use too many Cafergot Suppositories or someone else uses any of your medicine, you should tell your doctor at once or contact your nearest accident and emergency department. Show any left-over medicines or the empty packet to the doctor.

Symptoms of an overdose include feeling or being sick, drowsiness, dizziness or confusion, having a slow or fast heartbeat, difficulty breathing, convulsions, tingling or numbness in your fingers or toes, your fingers turning blue, difficulty in passing urine or severe headache.

If you forget to use Cafergot Suppositories

Do not worry. If you forget to use a dose, use it as soon as possible, unless it is almost time to use the next dose. Do not use a double dose. Then go on as before.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Cafergot Suppositories Side Effects

Do not worry. Like all medicines, Cafergot Suppositories can cause side effects, although not everyone gets them.

If you experience severe numbness or tingling in your hands or feet, nausea, vomiting, pains in your chest or are passing less urine than normal, stop taking Cafergot Suppositories and contact a doctor or go to the nearest hospital straight away as you may need urgent medical attention.

Common side effects (that affect less than 1 person in 10):

• feeling or actually being sick


• stomach pain


• dizziness.

Uncommon side effects (that affect less than 1 person in 100):

• poor circulation in your hands or feet which can make them feel cold or painful and look pale or blue


• pain or weakness in your arms, hands, legs or feet


• tingling or numbness in your hands or feet


• diarrhoea.

Rare side effects (that affect less than 1 person in 1000):

• allergic reactions that may include itchy rash, swelling of the face, difficulty breathing, nettle rash


• slow or fast heartbeat


• high blood pressure


• muscle pain


• headache


• stroke (causing sudden weakness or numbness, dizziness or severe headache)


• changes in blood tests which show how the kidneys are working.

Very rare side effects (that affect less than 1 person in 10 000):

• angina or heart attack (causing pain in the chest)


• gangrene (when the blood supply to extremities such as toes or fingers is cut off).

The caffeine in Cafergot Suppositories may cause the following unwanted side effects:

• feeling of anxiety


• trembling


• sweating


• fast heartbeat.

Cafergot Suppositories sometimes cause the following side effects in some people:

• rectal and anal ulcers.

If any of the side effects gets worse, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Cafergot Suppositories

Keep out of the reach and sight of children.

Do not use Cafergot Suppositories after the expiry date which is stated on the carton (EXPIRY). The expiry date refers to the last day of that month.

Do not store above 25°C

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist on how to dispose of medicines no longer required. These measures will help protect the environment.

Further information

What is in Cafergot Suppositories?

The active ingredients in this medicine are ergotamine tartrate and caffeine.

The other ingredients are: tartaric acid, lactose and suppocire AM.

What Cafergot Suppositories look like and contents of the pack

Cafergot Suppositories are off-white suppositories.

Cafergot Suppositories come in packs of 30.

Marketing Authorisation Holder and Manufacturer

The product licence holder is:

Alliance Pharmaceuticals Ltd

Avonbridge House

Chippenham

Wiltshire

SN15 2BB

UK

Cafergot Suppositories are manufactured by:

Novartis Pharmaceuticals Ltd

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

UK

The information in this leaflet applies only to Cafergot Suppositories. If you have any questions or you are not sure about anything, ask your doctor or a pharmacist.

This leaflet was last approved: 30th March 2009

Alliance and associated devices are registered Trademarks of Alliance Pharmaceuticals Limited.

Cafergot Suppositories is a registered trademark of Novartis Pharmaceuticals Ltd and is used under licence by Alliance Pharmaceuticals Limited.

© Alliance Pharmaceuticals Ltd 2009.

UK 006