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DRUGS & SUPPLEMENTS
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Jackson's Lemon Linctus
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Jackson's Lemon Linctus uses
Jackson's Lemon Linctus consists of Glycerol, Honey.Glycerol:
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
| Indications and Usage (1) | 04/2017 |
| Dosage and Administration (2.1) | 04/2017 |
| Dosage and Administration (2.2) | 04/2017 |
Jackson's Lemon Linctus (Glycerol) is indicated for use as a nitrogen-binding agent for chronic management of patients 2 months of age and older with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Jackson's Lemon Linctus (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
Limitations of Use:
- Jackson's Lemon Linctus (Glycerol) is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels.
- The safety and efficacy of Jackson's Lemon Linctus (Glycerol) for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.
Jackson's Lemon Linctus (Glycerol) is a nitrogen-binding agent indicated for chronic management of patients 2 months of age and older with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Jackson's Lemon Linctus (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements. (1)
Limitations of Use:
- Jackson's Lemon Linctus (Glycerol) is not indicated for treatment of acute hyperammonemia in patients with UCDs. (1)
- Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. (1)
2 DOSAGE AND ADMINISTRATION
- Jackson's Lemon Linctus should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. (2.1, 2.6)
Switching From Sodium Phenylbutyrate Tablets or Powder to Jackson's Lemon Linctus (Glycerol):
- Patients should receive the dosage of Jackson's Lemon Linctus (Glycerol) that contains the same amount of phenylbutyric acid, see full prescribing information for conversion. (2.2)
Initial Dosage in Phenylbutyrate-Naïve Patients (2.3):
- Recommended dosage range is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day).
- For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m2/day.
- Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence.
Dosage Adjustment and Monitoring:
- Follow plasma ammonia levels to determine the need for dosage titration. (2.4)
Dosage Modifications in Patients with Hepatic Impairment:
- Start dosage at lower end of range. (2.5, 8.6)
2.1 Important Administration Instructions
Jackson's Lemon Linctus (Glycerol) should be prescribed by a physician experienced in the management of UCDs.
- Instruct patients to take Jackson's Lemon Linctus (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
- For patients who cannot swallow, see the instructions on administration of Jackson's Lemon Linctus (Glycerol) by nasogastric tube or gastrostomy tube .
- For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels .
- The recommended dosages for patients switching from sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol) and patients naïve to phenylbutyric acid are different . For both subpopulations:
- Patients 2 years of age and older: Give Jackson's Lemon Linctus (Glycerol) in 3 equally divided dosages, each rounded up to the nearest 0.5 mL
- Patients 2 months of age to less than 2 years: Give Jackson's Lemon Linctus (Glycerol) in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL.
- The maximum total daily dosage is 17.5 mL (19 g).
- Jackson's Lemon Linctus (Glycerol) must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
2.2 Switching From Sodium Phenylbutyrate to Jackson's Lemon Linctus
Patients switching from sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol) should receive the dosage of Jackson's Lemon Linctus (Glycerol) that contains the same amount of phenylbutyric acid. The conversion is as follows:
Total daily dosage of Jackson's Lemon Linctus (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86
Total daily dosage of Jackson's Lemon Linctus (Glycerol) (mL) = total daily dosage of sodium phenylbutyrate powder (g) × 0.81
2.3 Initial Dosage in Phenylbutyrate-Naïve Patients
The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m2/day.
In determining the starting dosage of Jackson's Lemon Linctus (Glycerol) in treatment-naïve patients, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated Jackson's Lemon Linctus (Glycerol) dose for a 24-hour period is 0.6 mL Jackson's Lemon Linctus (Glycerol) per gram of dietary protein ingested per 24-hour period. The total daily dosage should not exceed 17.5 mL.
2.4 Dosage Adjustment and Monitoring
During treatment with Jackson's Lemon Linctus (Glycerol), patients should be followed clinically and with plasma ammonia levels to determine the need for dosage titration. Closely monitor ammonia levels after changing the dosage of Jackson's Lemon Linctus (Glycerol).
Normal Ammonia Levels
If patients experience symptoms of vomiting, nausea, headache, somnolence or confusion in the absence of high ammonia levels or other intercurrent illnesses, reduce the Jackson's Lemon Linctus (Glycerol) dosage and monitor patients clinically. If available, obtain measurements of plasma phenylacetate (PAA) concentrations and the ratio of plasma PAA to PAGN to guide dosing. A high PAA to PAGN ratio may indicate the saturation of the conjugation reaction to form PAGN. The PAA to PAGN ratio has been observed to be generally less than 1 in patients with UCDs without significant PAA accumulation .
Elevated Ammonia Levels
When plasma ammonia is elevated, increase the Jackson's Lemon Linctus (Glycerol) dosage to reduce the fasting ammonia level to less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and pediatric patients (generally below 6 years of age), where obtaining fasting ammonia is problematic due to frequent feedings, adjust the dosage to keep the first ammonia of the morning below the ULN.
Urinary Phenylacetylglutamine: If available, U-PAGN measurements may be used to help guide Jackson's Lemon Linctus (Glycerol) dosage adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the Jackson's Lemon Linctus (Glycerol) dosage should be adjusted upward. The amount of dosage adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN level and the estimated Jackson's Lemon Linctus (Glycerol) dose needed per gram of dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL).
Consider a patient's use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN .
Plasma Phenylacetate and Phenylacetylglutamine: If available, the ratio of PAA to PAGN in plasma may provide additional information to assist in dosage adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in Jackson's Lemon Linctus (Glycerol) dosage may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction .
2.5 Dosage Modifications in Patients with Hepatic Impairment
For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range and kept at the lowest dose necessary to control the patient's ammonia levels .
2.6 Preparation for Nasogastric Tube or Gastrostomy Tube Administration
It is recommended that all patients who can swallow take Jackson's Lemon Linctus (Glycerol) orally, even those with nasogastric and/or gastrostomy tubes. However, for patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer Jackson's Lemon Linctus (Glycerol) as follows:
- Utilize an oral syringe to withdraw the prescribed dosage of Jackson's Lemon Linctus (Glycerol) from the bottle.
- Place the tip of the syringe into the nasogastric/gastrostomy tube.
- Utilizing the plunger of the syringe, administer Jackson's Lemon Linctus (Glycerol) into the tube.
- Flush once with 10 mL of water or formula and allow the flush to drain.
- If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.
For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of Jackson's Lemon Linctus (Glycerol) to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of Jackson's Lemon Linctus (Glycerol) dosing or dosage adjustments.
3 DOSAGE FORMS AND STRENGTHS
Oral liquid: colorless to pale yellow, 1.1 g/mL of Jackson's Lemon Linctus (Glycerol) phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).
Oral liquid: 1.1 g/mL. (3)
4 CONTRAINDICATIONS
Jackson's Lemon Linctus (Glycerol) is contraindicated in patients
- Less than 2 months of age. Pediatric patients less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of Jackson's Lemon Linctus (Glycerol), leading to impaired absorption of phenylbutyrate and hyperammonemia .
- With known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.
- Patients less than 2 months of age. (4)
- Known hypersensitivity to phenylbutyrate. (4)
5 WARNINGS AND PRECAUTIONS
- Neurotoxicity: Phenylacetate, the active moiety of Jackson's Lemon Linctus (Glycerol), may be toxic; reduce dosage for symptoms of neurotoxicity. (5.1)
- Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely. (5.2)
5.1 Neurotoxicity
The major metabolite of Jackson's Lemon Linctus (Glycerol), PAA, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy, were observed at plasma PAA concentrations of 500 micrograms/mL in a study of adult cancer patients who were administered PAA intravenously. In this study, adverse reactions were reversible.
In healthy subjects, after administration of 4 mL and 6 mL Jackson's Lemon Linctus (Glycerol) 3 times daily for 3 days, a dose-dependent increase in all-grade nervous system adverse reactions was observed, even at exposure levels of PAA less than 100 micrograms/mL.
In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of Jackson's Lemon Linctus (Glycerol), peak PAA concentrations after dosing with Jackson's Lemon Linctus (Glycerol) ranged from 1.6 to 178 micrograms/mL (mean: 39 micrograms/mL) in adult patients, from 1 to 410 micrograms/mL (mean: 70 micrograms/mL; median: 50 micrograms/mL) in pediatric patients ages 2 years and older, and from 1 to 1215 micrograms/mL (mean: 142 micrograms/mL; median: 35 micrograms/mL) in pediatric patients ages 2 months to less than 2 years. Some patients with UCDs experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were generally not measured at the time of neurotoxicity symptoms.
If symptoms of vomiting, nausea, headache, somnolence or confusion, are present in the absence of high ammonia or other intercurrent illnesses, reduce the Jackson's Lemon Linctus (Glycerol) dosage .
5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption
Exocrine pancreatic enzymes hydrolyze Jackson's Lemon Linctus (Glycerol) in the small intestine, separating the active moiety, phenylbutyrate, from Jackson's Lemon Linctus (Glycerol). This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of Jackson's Lemon Linctus (Glycerol) and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
6 ADVERSE REACTIONS
Most common adverse reactions in adults are: diarrhea, flatulence, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Horizon Therapeutics at 1-855-823-7878 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older . One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction.
The most common adverse reactions (occurring in at least 10% of patients) reported during short-term treatment with Jackson's Lemon Linctus (Glycerol) were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Jackson's Lemon Linctus (Glycerol) or sodium phenylbutyrate (incidence of at least 4% in either treatment arm).
| Number (%) of Patients in Study 1 | ||
|---|---|---|
| Sodium Phenylbutyrate (N = 45) | Jackson's Lemon Linctus (Glycerol) (N = 44) | |
| Diarrhea | 3 (7) | 7 (16) |
| Headache | 4 (9) | 6 (14) |
| Flatulence | 1 (2) | 6 (14) |
| Abdominal pain | 2 (4) | 3 (7) |
| Vomiting | 2 (4) | 3 (7) |
| Decreased appetite | 2 (4) | 3 (7) |
| Fatigue | 1 (2) | 3 (7) |
| Dyspepsia | 3 (7) | 2 (5) |
| Nausea | 3 (7) | 1 (2) |
| Dizziness | 4 (9) | 0 |
| Abdominal discomfort | 3 (7) | 0 |
Other Adverse Reactions
Jackson's Lemon Linctus (Glycerol) has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with Jackson's Lemon Linctus (Glycerol) (median exposure = 51 weeks). During these studies there were no deaths.
Adverse reactions occurring in at least 10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue.
Adverse reactions occurring in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.
Jackson's Lemon Linctus (Glycerol) has also been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies. The median exposure was 6 months (range 0.2 to 18 months). Adverse reactions occurring in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash and papule.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Jackson's Lemon Linctus (Glycerol). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- Abnormal body odor, including from skin, hair and urine
- Retching and gagging
- Dysgeusia or burning sensation in mouth
7 DRUG INTERACTIONS
- Corticosteroids, valproic acid, or haloperidol: May increase plasma ammonia level; monitor ammonia levels closely.
- Probenecid: May affect renal excretion of metabolites of Jackson's Lemon Linctus (Glycerol), including phenylacetylglutamine (PAGN) and PAA. (7.2)
- CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine): Jackson's Lemon Linctus (Glycerol) may decrease exposure; monitor for decreased efficacy of the narrow therapeutic index drug. (7.3)
- Midazolam: Decreased exposure; monitor for suboptimal effect of midazolam. (7.3)
7.1 Potential for Other Drugs to Affect Ammonia
Corticosteroids
Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and Jackson's Lemon Linctus (Glycerol) are used concomitantly.
Valproic Acid and Haloperidol
Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs.
7.2 Potential for Other Drugs to Affect Jackson's Lemon Linctus
Probenecid
Probenecid may inhibit the renal excretion of metabolites of Jackson's Lemon Linctus (Glycerol) including PAGN and PAA.
7.3 Potential for Jackson's Lemon Linctus to Affect Other Drugs
Drugs with narrow therapeutic index that are substrates of CYP3A4
Jackson's Lemon Linctus (Glycerol) is a weak inducer of CYP3A4 in humans. Concomitant use of Jackson's Lemon Linctus (Glycerol) may decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) .
Midazolam
Concomitant use of Jackson's Lemon Linctus (Glycerol) decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with Jackson's Lemon Linctus (Glycerol).
8 USE IN SPECIFIC POPULATIONS
Lactation: Breastfeeding is not recommended.
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Jackson's Lemon Linctus (Glycerol) during pregnancy. Healthcare providers are encouraged to report any prenatal exposure to Jackson's Lemon Linctus (Glycerol) by calling the Pregnancy Registry at 1-855-823-2595 or visiting www.ucdregistry.com.
Risk Summary
Limited available data with Jackson's Lemon Linctus (Glycerol) use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral Jackson's Lemon Linctus (Glycerol) phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7–times the dose of 6.87 mL/m2/day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal development. In addition, there were no adverse developmental effects with administration of oral Jackson's Lemon Linctus (Glycerol) phenylbutyrate to pregnant rats during organogenesis at 1.9 times the dose of 6.87 mL/m2/day in adult patients; however, maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in pregnant rats administered oral Jackson's Lemon Linctus (Glycerol) phenylbutyrate during organogenesis at doses greater than or equal to 5.7 times the dose of 6.87 mL/m2/day in adult patients [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Oral administration of Jackson's Lemon Linctus (Glycerol) phenylbutyrate during the period of organogenesis up to 350 mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of 6.87 mL/m2/day in adult patients, based on combined area under the plasma concentration-time curve [AUCs] for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of Jackson's Lemon Linctus (Glycerol) phenylbutyrate (1.9 times the dose of 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity and adverse effects on embryo-fetal development including reduced fetal weights and cervical ribs at the 7th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately 5.7 times the dose of 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA. No developmental abnormalities, effects on growth, or effects on learning and memory were observed through maturation of offspring following oral administration in pregnant rats with up to 900 mg/kg/day of Jackson's Lemon Linctus (Glycerol) phenylbutyrate (8.5 times the dose of 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation.
8.2 Lactation
Risk Summary
There are no data on the presence of Jackson's Lemon Linctus in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Jackson's Lemon Linctus (Glycerol).
8.4 Pediatric Use
Safety and efficacy of Jackson's Lemon Linctus (Glycerol) have been established in pediatric patients 2 months of age and older with UCDs.
Jackson's Lemon Linctus (Glycerol) is contraindicated in pediatric patients less than 2 months of age .
Patients 2 Years to Less Than 18 Years of Age
The safety and efficacy of Jackson's Lemon Linctus (Glycerol) in patients 2 years to less than 18 years of age were established in 2 open-label, sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol), fixed-sequence, switchover clinical studies .
Patients 2 Months to Less Than 2 Years of Age
The safety and efficacy of Jackson's Lemon Linctus (Glycerol) in patients with UCDs, 2 months to less than 2 years of age were established in 3 open-label studies. Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients between 2 months and less than 2 years of age .
Patients Less Than 2 Months of Age
Jackson's Lemon Linctus (Glycerol) is contraindicated in patients less than 2 months of age . Pediatric patients less than 2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of Jackson's Lemon Linctus (Glycerol). Pancreatic lipases may be necessary for intestinal hydrolysis of Jackson's Lemon Linctus (Glycerol), allowing release of phenylbutyrate and subsequent formation of PAA, the active moiety. It is not known whether pancreatic and extrapancreatic lipases are sufficient for hydrolysis of Jackson's Lemon Linctus (Glycerol). If there is inadequate intestinal hydrolysis of Jackson's Lemon Linctus (Glycerol), impaired absorption of phenylbutyrate and hyperammonemia could occur.
Juvenile Animal Toxicity Data
In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced by up to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA). Learning, memory, and motor activity endpoints were not affected. However, fertility (number of pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA).
8.5 Geriatric Use
Clinical studies of Jackson's Lemon Linctus did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than 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 decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
The efficacy and safety of Jackson's Lemon Linctus (Glycerol) in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on Jackson's Lemon Linctus (Glycerol).
8.7 Hepatic Impairment
No studies were conducted in patients with UCDs and hepatic impairment. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion capability and higher plasma PAA and PAA to PAGN ratio . Therefore, dosage for patients with moderate to severe hepatic impairment should be started at the lower end of the recommended dosing range and should be kept on the lowest dose necessary to control their ammonia levels .
10 OVERDOSAGE
While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of Jackson's Lemon Linctus (Glycerol), can accumulate in patients who receive an overdose .
If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
11 DESCRIPTION
Jackson's Lemon Linctus (Glycerol) (glycerol phenylbutyrate) is a clear, colorless to pale yellow oral liquid. It is insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO) and greater than 65% acetonitrile.
Jackson's Lemon Linctus (Glycerol) phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3 molecules of PBA linked to a Jackson's Lemon Linctus (Glycerol) backbone, the chemical name of which is benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It has a molecular formula of C33H38O6. The structural formula is:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia. Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Jackson's Lemon Linctus (Glycerol) is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Jackson's Lemon Linctus (Glycerol). PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.
Figure 1: RAVICTI Mechanism of Action
12.2 Pharmacodynamics
Pharmacological Effects
In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia concentration was comparable at steady state during the switchover period between Jackson's Lemon Linctus (Glycerol) and sodium phenylbutyrate .
Cardiac Electrophysiology
The effect of multiple doses of Jackson's Lemon Linctus (Glycerol) 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects. The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for Jackson's Lemon Linctus (Glycerol), was below 10 ms. However, assay sensitivity was not established in this study because the moxifloxacin time-profile was not consistent with expectation. Therefore, an increase in mean QTc interval of 10 ms cannot be ruled out.
12.3 Pharmacokinetics
Absorption
Jackson's Lemon Linctus (Glycerol) is a pro-drug of PBA. Upon oral ingestion, PBA is released from the Jackson's Lemon Linctus (Glycerol) backbone in the gastrointestinal tract by lipases. PBA derived from Jackson's Lemon Linctus (Glycerol) is further converted by β-oxidation to PAA.
In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m2 of Jackson's Lemon Linctus (Glycerol), peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of Jackson's Lemon Linctus (Glycerol), plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (Cmax) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact Jackson's Lemon Linctus (Glycerol) phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of Jackson's Lemon Linctus (Glycerol) phenylbutyrate cannot be ruled out.
In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. Following 4 mL of Jackson's Lemon Linctus (Glycerol) 3 times a day for 3 days, the mean Cmax and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of Jackson's Lemon Linctus (Glycerol) three times a day for 3 days, mean Cmax and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively.
In adult patients with UCDs receiving multiple doses of Jackson's Lemon Linctus (Glycerol), maximum plasma concentrations at steady state (Cmax,ss) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. Intact Jackson's Lemon Linctus (Glycerol) phenylbutyrate was not detectable in plasma in patients with UCDs.
Distribution
In vitro, the extent of plasma protein binding for 14C-labeled metabolites was 81% to 98% for PBA (over 1 to 250 micrograms/mL), and 37% to 66% for PAA (over 5 to 500 micrograms/mL). The protein binding for PAGN was 7% to 12% and no concentration effects were noted.
Elimination
Metabolism
Upon oral administration, pancreatic lipases hydrolyze Jackson's Lemon Linctus (Glycerol) (i.e., Jackson's Lemon Linctus (Glycerol) phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.
Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment.
In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days, the ratio of mean AUC0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean Cmax values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7.
In in vitro studies, the specific activity of lipases for Jackson's Lemon Linctus (Glycerol) phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, Jackson's Lemon Linctus (Glycerol) phenylbutyrate was hydrolyzed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of Jackson's Lemon Linctus (Glycerol) phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in humans.
Excretion
The mean (SD) percentage of administered PBA excreted as PAGN was approximately 69% (17) in adults and 66% (24) in pediatric patients with UCDs at steady state. PAA and PBA represented minor urinary metabolites, each accounting for less than 1% of the administered dose of PBA.
Specific Populations
Age: Pediatric Population
Population pharmacokinetic modeling and dosing simulations suggest body surface area to be the most significant covariate explaining the variability of PAA clearance. PAA clearance was 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for patients ages 3 to 5, 6 to 11, and 12 to 17 years with UCDs.
In pediatric patients with UCDs (n = 14) ages 2 months to less than 2 years, PAA clearance was 6.8 L/h.
Sex
In healthy adult subjects, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level. In healthy female subjects, mean Cmax for PAA was 51 and 120% higher than in male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively. The dose normalized mean AUC0-23h for PAA was 108% higher in females than in males.
Renal Impairment
The pharmacokinetics of Jackson's Lemon Linctus (Glycerol) in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis, have not been studied .
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of Jackson's Lemon Linctus (Glycerol) were studied in patients with mild, moderate and severe hepatic impairment of (Child-Pugh class A, B, and C, respectively) receiving 100 mg/kg of Jackson's Lemon Linctus (Glycerol) twice daily for 7 days.
Plasma Jackson's Lemon Linctus (Glycerol) phenylbutyrate was not measured in patients with hepatic impairment.
After multiple doses of Jackson's Lemon Linctus (Glycerol) in patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUCt of PBA was 42%, 84%, and 50% higher, respectively, while geometric mean AUCt of PAA was 22%, 53%, and 94% higher, respectively, than in healthy subjects.
In patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUCt of PAGN was 42%, 27%, and 22% lower, respectively, than that in healthy subjects.
The proportion of PBA excreted as PAGN in the urine in Child-Pugh A, B, and C was 80%, 58%, and 85%, respectively, and, in healthy volunteers, was 67%.
In another study in patients with moderate and severe hepatic impairment (Child-Pugh B and C), mean Cmax of PAA was 144 micrograms/mL (range: 14 to 358 micrograms/mL) after daily dosing of 6 mL of Jackson's Lemon Linctus (Glycerol) twice daily, while mean Cmax of PAA was 292 micrograms/mL (range: 57 to 655 micrograms/mL) after daily dosing of 9 mL of Jackson's Lemon Linctus (Glycerol) twice daily. The ratio of mean Cmax values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7, respectively.
After multiple doses, a PAA concentration greater than 200 micrograms/mL was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5 .
Drug Interaction Studies
In vitro PBA or PAA did not induce CYP1A2, suggesting that in vivo drug interactions via induction of CYP1A2 is unlikely.
In in vitro studies, PBA at a concentration of 800 micrograms/mL caused greater than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5 (testosterone 6β-hydroxylase activity). The in vitro study suggested that in vivo drug interactions with substrates of CYP2D6 cannot be ruled out. The inhibition of CYP isoenzymes 1A2, 2C8, 2C19, and 2D6 by PAA at the concentration of 2.8 mg/mL was observed in vitro. Clinical implication of these results is unknown.
Effects of Jackson's Lemon Linctus (Glycerol) on other drugs
Midazolam
In healthy subjects, when oral midazolam was administered after multiple doses of Jackson's Lemon Linctus (Glycerol) (4 mL three times a day for 3 days) under fed conditions, the mean Cmax and AUC for midazolam were 25% and 32% lower, respectively, compared to administration of midazolam alone. In addition the mean Cmax and AUC for 1-hydroxy midazolam were 28% and 58% higher, respectively, compared to administration of midazolam alone .
Celecoxib
Concomitant administration of Jackson's Lemon Linctus (Glycerol) did not significantly affect the pharmacokinetics of celecoxib, a substrate of CYP2C9. When 200 mg of celecoxib was orally administered with Jackson's Lemon Linctus (Glycerol) after multiple doses of Jackson's Lemon Linctus (Glycerol) (4 mL three times a day for 6 days) under fed conditions (a standard breakfast was consumed 5 minutes after celecoxib administration), the mean Cmax and AUC for celecoxib were 13% and 8% lower than after administration of celecoxib alone.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In a 2-year study in Sprague-Dawley rats, Jackson's Lemon Linctus (Glycerol) phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma at a dose of 650 mg/kg/day in males (4.7 times the dose of 6.9 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA) and 900 mg/kg/day in females (8.4 times the dose of 6.9 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA). The incidence of the following tumors was also increased in female rats at a dose of 900 mg/kg/day: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial stromal polyp, and combined polyp or sarcoma. The dose of 650 mg/kg/day in male rats is 3 times the dose of 7.5 mL/m2/day in pediatric patients, based on combined AUCs for PBA and PAA. The dose of 900 mg/kg/day in female rats is 5.5 times the dose of 7.5 mL/m2/day in pediatric patients, based on combined AUCs for PBA and PAA. In a 26-week study in transgenic (Tg.rasH2) mice, Jackson's Lemon Linctus (Glycerol) phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day.
Mutagenesis
Jackson's Lemon Linctus (Glycerol) phenylbutyrate was not genotoxic in the Ames test, the in vitro chromosomal aberration test in human peripheral blood lymphocytes, or the in vivo rat micronucleus test. The metabolites PBA, PAA, PAGN, and phenylacetylglycine were not genotoxic in the Ames test or in vitro chromosome aberration test in Chinese hamster ovary cells.
Impairment of Fertility
Jackson's Lemon Linctus (Glycerol) phenylbutyrate had no effect on fertility or reproductive function in male and female rats at oral doses up to 900 mg/kg/day. At doses of 1200 mg/kg/day (approximately 7 times the dose of 6.9 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA), maternal toxicity was observed and the number of nonviable embryos was increased.
14 CLINICAL STUDIES
14.1 Clinical Studies in Adult Patients with UCDs
Active-Controlled, 4-Week, Noninferiority Study
A randomized, double-blind, active-controlled, crossover, noninferiority study (Study 1) compared Jackson's Lemon Linctus (Glycerol) to sodium phenylbutyrate by evaluating venous ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrollment for control of their UCD. Patients were required to have a confirmed diagnosis of UCD involving deficiencies of CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing. Patients had to have no clinical evidence of hyperammonemia at enrollment and were not allowed to receive drugs known to increase ammonia levels (e.g., valproate), increase protein catabolism (e.g., corticosteroids), or significantly affect renal clearance (e.g., probenecid).
The primary endpoint was the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28 when the drugs were expected to be at steady state. Statistical noninferiority would be established if the upper limit of the 2-sided 95% CI for the ratio of the geometric means (RAVICTI/sodium phenylbutyrate) for the endpoint was 1.25 or less.
Forty-five patients were randomized 1:1 to 1 of 2 treatment arms to receive either
- Sodium phenylbutyrate for 2 weeks → Jackson's Lemon Linctus (Glycerol) for 2 weeks; or
- Jackson's Lemon Linctus (Glycerol) for 2 weeks → sodium phenylbutyrate for 2 weeks.
Sodium phenylbutyrate or Jackson's Lemon Linctus (Glycerol) were administered three times daily with meals. The dose of Jackson's Lemon Linctus (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the study. Forty-four patients received at least 1 dose of Jackson's Lemon Linctus (Glycerol) in the study.
Patients adhered to a low-protein diet and received amino acid supplements throughout the study. After 2 weeks of dosing, by which time patients had reached steady state on each treatment, all patients had 24 hours of ammonia measurements.
Demographic characteristics of the 45 patients enrolled in Study 1 were as follows: mean age at enrollment was 33 years (range: 18 to 75 years); 69% were female; 33% had adult-onset disease; 89% had OTC deficiency; 7% had ASS deficiency; 4% had CPS deficiency.
Jackson's Lemon Linctus (Glycerol) was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Forty-four patients were evaluated in this analysis. Mean 24-hour AUCs for venous ammonia during steady-state dosing were 866 micromol∙h/L and 977 micromol∙h/L with Jackson's Lemon Linctus (Glycerol) and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91 [95% CI 0.8, 1.04].
The mean venous ammonia levels over 24-hours after 2 weeks of dosing (on day 14 and 28) in the double-blind short-term study (Study 1) are displayed in Figure 2 below. The mean and median maximum venous ammonia concentration (Cmax) over 24 hours and 24-hour AUC for venous ammonia are summarized in Table 2. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:
Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)
Figure 2: Venous Ammonia Response in Adult Patients with UCDs in Short-Term Treatment Study 1
| Timepoint | Ammonia (n=44) | |
|---|---|---|
| Mean (SD) | Median (min, max) | |
| Daily Cmax (micromol/L) | ||
| RAVICTI | 61 (46) | 51 (12, 245) |
| Sodium phenylbutyrate | 71 (67) | 46 (14, 303) |
| 24-Hour AUC (micromol∙h/L) | ||
| RAVICTI | 866 (661) | 673 (206, 3351) |
| Sodium phenylbutyrate | 977 (865) | 653 (302, 4666) |
Open-Label, Uncontrolled, Extension Study in Adults
A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol). Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults in Study 2 were within normal limits during long-term treatment with Jackson's Lemon Linctus (Glycerol) (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with Jackson's Lemon Linctus (Glycerol), 7 patients (14%) reported a total of 10 hyperammonemic crises. The fasting venous ammonia measured during Study 2 is displayed in Figure 3. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.
Figure 3: Venous Ammonia Response in Adult Patients with UCDs in Long-Term Treatment Study 2
Open-Label, Long-Term Study in Adults
An open-label long-term, study (Study 5) was conducted to assess ammonia control in adult patients with UCDs. The study enrolled patients with UCDs who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 43 adult patients between the ages of 19 and 61 years were in the study. The median length of study participation was 1.9 years (range 0 to 4.5 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean fasting venous ammonia values in adult patients in Study 5 were within normal limits during long-term (24 months) treatment with Jackson's Lemon Linctus (Glycerol) (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with Jackson's Lemon Linctus (Glycerol), 9 patients (21%) reported a total of 21 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.
14.2 Clinical Studies in Pediatric Patients Ages 2 to 17 Years with UCDs
The efficacy of Jackson's Lemon Linctus (Glycerol) in pediatric patients 2 to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol) switchover studies (Studies 3 and 4). Study 3 was 7 days in duration and Study 4 was 10 days in duration.
These studies compared blood ammonia levels of patients on Jackson's Lemon Linctus (Glycerol) to venous ammonia levels of patients on sodium phenylbutyrate in 26 pediatric patients between 2 months and 17 years of age with UCDs. Four patients less than 2 years of age are excluded for this analysis due to insufficient data. The dose of Jackson's Lemon Linctus (Glycerol) was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate patients were taking when they entered the trial. Sodium phenylbutyrate or Jackson's Lemon Linctus (Glycerol) were administered in divided doses with meals. Patients adhered to a low-protein diet throughout the study. After a dosing period with each treatment, all patients underwent 24 hours of venous ammonia measurements, as well as blood and urine pharmacokinetic assessments.
UCD subtypes included OTC (n=12), argininosuccinate lyase (ASL) (n=8), and ASS deficiency (n=2), and patients received a mean Jackson's Lemon Linctus (Glycerol) dose of 8 mL/m2/day (8.8 g/m2/day), with doses ranging from 1.4 to 13.1 mL/m2/day (1.5 to 14.4 g/m2/day). Doses in these patients were based on previous dosing of sodium phenylbutyrate.
The 24-hour AUCs for blood ammonia (AUC0-24h) in 11 pediatric patients 6 to 17 years of age with UCDs (Study 3) and 11 pediatric patients 2 years to 5 years of age with UCDs (Study 4) were similar between treatments. In children 6 to 17 years of age, the ammonia AUC0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on Jackson's Lemon Linctus (Glycerol) vs sodium phenylbutyrate. In the patients between 2 years and 5 years of age with UCDs, the ammonia AUC0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on Jackson's Lemon Linctus (Glycerol) versus sodium phenylbutyrate.
The mean venous ammonia levels over 24 hours in open-label, short-term Studies 3 and 4 at common time points are displayed in Figure 4. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:
Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)
Figure 4: Venous Ammonia Response in Pediatric Patients Ages 2 to 17 Years with UCDs in Short-Term Treatment Studies 3 and 4
Open-Label, Uncontrolled, Extension Studies in Children Ages 2 to 17 Years
Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. In two studies (Study 2, which also enrolled adults, and an extension of Study 3, referred to here as Study 3E), a total of 26 children ages 6 to 17 were enrolled and all but 1 had been converted from sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol). Mean fasting venous ammonia values were within normal limits during long-term treatment with Jackson's Lemon Linctus (Glycerol) (range: 17 to 23 micromol/L). Of the 26 pediatric patients 6 to 17 years of age participating in these two trials, 5 patients (19%) reported a total of 5 hyperammonemic crises. The fasting venous ammonia measured during these two extension studies in patients 6 to 17 years is displayed in Figure 5. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.
Figure 5: Venous Ammonia Response in Pediatric Patients Ages 2 to 17 Years with UCDs in Long-Term Treatment Studies 2 and 3E
In an extension of Study 4, after a median time on study of 4.5 months (range: 1 to 5.7 months), 2 of 16 pediatric patients ages 2 to 5 years had experienced three hyperammonemic crises.
Open-Label, Long-Term Study in Children Ages 1 to 17 Years of Age
An open-label, long-term study (Study 5) was conducted to assess ammonia control in pediatric patients with UCD. The study enrolled patients with UCD who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 45 pediatric patients between the ages of 1 and 17 years were in the study. The median length of study participation was 1.7 years (range 0.2 to 4.6 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean venous ammonia values in pediatric patients in Study 5 were within normal limits during long-term (24 months) treatment with Jackson's Lemon Linctus (Glycerol) (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with Jackson's Lemon Linctus (Glycerol), 11 patients (24%) reported a total of 22 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.
14.3 Clinical Studies in Pediatric Patients Ages 2 Months to Less Than 2 Years with UCDs
Uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crisis of Jackson's Lemon Linctus (Glycerol) in pediatric patients with UCDs 2 months to less than 2 years of age (Study 4/4E, Study 5, and Study 6). Patients in Study 5 previously participated in Study 4/4E. A total of 17 pediatric patients with UCDs aged 2 months to less than 2 years participated in the studies.
Uncontrolled, Open-Label Study in Children Under 2 Years of Age (Study 6)
A total of 10 pediatric patients with UCDs aged 2 months to less than 2 years participated in Study 6, of which 7 patients converted from sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol). The dosage of Jackson's Lemon Linctus (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the trial. Two patients were treatment naïve and received Jackson's Lemon Linctus (Glycerol) dosage of 7.5 mL/m2/day and 9.4 mL/m2/day, respectively. One additional patient was gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while Jackson's Lemon Linctus (Glycerol) was initiated. The dosage of Jackson's Lemon Linctus (Glycerol) after transition was 8.5 mL/m2/day.
In Study 6, there were 9, 7 and 3 pediatric patients who completed 1, 3 and 6 months, respectively (mean and median exposure of 4 and 5 months, respectively).
Patients received a mean Jackson's Lemon Linctus (Glycerol) dose of 8 mL/m2/day (8.8 g/m2/day), with doses ranging from 4.8 to 11.5 mL/m2/day (5.3 to 12.6 g/m2/day). Patients were dosed three times a day (n=6), four times a day (n = 2), or five or more times a day (n=2).
The primary efficacy endpoint was successful transition to Jackson's Lemon Linctus (Glycerol) within a period of 4 days followed by 3 days of observation for a total of 7 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value less than 100 micromol/L. Venous ammonia levels were monitored for up to 4 days during transition and on day 7. Nine patients successfully transitioned as defined by the primary endpoint. One additional patient developed hyperammonemia on day 3 of dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement on day 4. This patient developed hyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated to drug. Although two patients had day 7 ammonia values of 150 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.
During the extension phase, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean normalized venous ammonia values in pediatric patients at month 1, 2, 3, 4, 5 and 6 were 67, 53, 78, 99, 56 and 61 micromol/L during treatment with Jackson's Lemon Linctus (Glycerol), respectively. Three patients reported a total of 7 hyperammonemic crises defined as having signs and symptoms consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high venous ammonia levels and requiring medical intervention. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract infection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events). There were three additional patients who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.
Uncontrolled, Open-Label Studies in Children Under 2 Years of Age (Studies 4/4E, 5)
A total of 7 patients with UCDs aged 2 months to less than 2 years participated in Studies 4/4E and 5. In these studies, there were 7, 6, 6, 6 and 3 pediatric patients who completed 1, 6, 9, 12 and 18 months, respectively (mean and median exposure of 15 and 17 months, respectively). Patients were converted from sodium phenylbutyrate to Jackson's Lemon Linctus (Glycerol). The dosage of Jackson's Lemon Linctus (Glycerol) was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the study.
Patients received a mean Jackson's Lemon Linctus (Glycerol) dose of 7.5 mL/m2/day (8.2 g/m2/day), with doses ranging from 3.3 to 12.3 mL/m2/day (3.7 to 13.5 g/m2/day). Patients were dosed three times a day (n=3) or four times a day (n = 4).
Venous ammonia levels were monitored on days 1, 3 and 10 in Study 4 and at week 1 in Study 4E. Two patients had day 1 ammonia values of 122 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia. At day 10/week 1, six of the 7 patients had venous ammonia levels less than 100 micromol/L the remaining patient had a day 10 ammonia value of 168 micromol/L and was asymptomatic.
During the extension period, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean venous ammonia values in pediatric patients at month 1, 3, 6, 9 and 12 were 58, 49, 34, 65, and 31 micromol/L during treatment with Jackson's Lemon Linctus (Glycerol), respectively.
Three patients reported a total of 3 hyperammonemic crises, as defined in Study 6. Hyperammonemic crises were precipitated by gastroenteritis, vomiting, infection or no precipitating event (one patient). There were 4 patients who had one venous ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.
16 HOW SUPPLIED/STORAGE AND HANDLING
Jackson's Lemon Linctus (Glycerol) ® (glycerol phenylbutyrate) oral liquid 1.1 g/mL is supplied in multi-use, 25-mL glass bottles. The bottles are supplied in the following configurations:
- NDC 75987-050-06: Single 25-mL bottle per carton
- NDC 75987-050-07: Four 25-mL bottles per carton
Store at 20°-25°C (68°-77°F) with excursions permitted to 15°-30°C (59°-86°F).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Neurotoxicity .
- Inform patients/caregivers that adverse reactions of Jackson's Lemon Linctus (Glycerol) are sometimes the same as symptoms of high blood ammonia. Neurological adverse events may also be associated with the major metabolite of Jackson's Lemon Linctus (Glycerol), PAA, and may be reversible. Blood tests for PAA may be done to measure the amount of PAA in the blood. Instruct the patient/caregiver to contact the healthcare provider immediately if the patient experiences: nausea, vomiting, headache, fatigue, somnolence, lightheadedness, confusion, exacerbation of preexisting neuropathy, disorientation, impaired memory, dysgeusia, or hypoacusis.
Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Jackson's Lemon Linctus (Glycerol) during pregnancy .
Lactation
Advise patients that breastfeeding is not recommended during treatment with Jackson's Lemon Linctus (Glycerol) .
Administration
- Instruct patients to take Jackson's Lemon Linctus (Glycerol) with food or formula and to administer directly into the mouth via oral syringe or dosing cup.
- Instruct patients to take Jackson's Lemon Linctus (Glycerol) orally, even if they have a nasogastric and/or gastrostomy tube. For patients who cannot swallow and who have a nasogastric tube or gastrostomy tube in place, instruct patients/caregivers to administer Jackson's Lemon Linctus (Glycerol) as follows:
- Utilize an oral syringe to withdraw the prescribed dosage of Jackson's Lemon Linctus (Glycerol) from the bottle.
- Place the tip of the syringe into the gastrostomy/nasogastric tube.
- Utilizing the plunger of the syringe, administer Jackson's Lemon Linctus (Glycerol) into the tube.
- Flush once with 10 mL of water or formula and allow the flush to drain.
- If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.
Distributed by:
Horizon Pharma USA, Inc.
Lake Forest, IL 60045
Horizon Therapeutics, LLC.
All rights reserved.
Jackson's Lemon Linctus (Glycerol) is a registered trademark of Horizon Therapeutics, LLC.
| MEDICATION GUIDE Jackson's Lemon Linctus (Glycerol) (rah-VIK- tee) (glycerol phenylbutyrate) oral liquid | ||
|---|---|---|
| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Revised: 04/2017 | |
| What is the most important information I should know about Jackson's Lemon Linctus (Glycerol)? Jackson's Lemon Linctus (Glycerol) may cause serious side effects, including: Nervous system problems (Neurotoxicity). Phenylacetate (PAA), a breakdown product of Jackson's Lemon Linctus (Glycerol), may cause nervous system side effects. Call your doctor or get medical help right away if you get any of these symptoms while taking Jackson's Lemon Linctus (Glycerol): | ||
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| Your doctor may do blood tests to measure the amount of PAA in your blood during your treatment with Jackson's Lemon Linctus (Glycerol). | ||
| What is Jackson's Lemon Linctus (Glycerol)?
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| Who should not take Jackson's Lemon Linctus (Glycerol)?
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| Before taking Jackson's Lemon Linctus (Glycerol), tell your doctor about any medical conditions and if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, dietary and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. | ||
| How should I take Jackson's Lemon Linctus (Glycerol)?
For people who cannot swallow and who have a nasogastric or gastrostomy tube in place, Jackson's Lemon Linctus (Glycerol) should be given as follows:
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| What are the possible side effects of Jackson's Lemon Linctus (Glycerol)? Jackson's Lemon Linctus (Glycerol) may cause serious side effects, including: | ||
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| The most common side effects of Jackson's Lemon Linctus (Glycerol) in adults include: | ||
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| The most common side effects of Jackson's Lemon Linctus (Glycerol) in children 2 years to 17 years of age include: | ||
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| The most common side effects of Jackson's Lemon Linctus (Glycerol) in children 2 months to less than 2 years of age include: | ||
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| Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Jackson's Lemon Linctus (Glycerol). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||
| How should I store Jackson's Lemon Linctus (Glycerol)?
Keep Jackson's Lemon Linctus (Glycerol) and all medicines out of the reach of children. | ||
| General information about the safe and effective use of Jackson's Lemon Linctus (Glycerol). Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Jackson's Lemon Linctus (Glycerol) for a condition for which it was not prescribed. Do not give Jackson's Lemon Linctus (Glycerol) to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about Jackson's Lemon Linctus (Glycerol) that is written for health professionals. | ||
| What are the ingredients in Jackson's Lemon Linctus (Glycerol)? Active ingredient: Jackson's Lemon Linctus (Glycerol) phenylbutyrate Distributed by: Horizon Pharma USA, Inc., Lake Forest, IL 60045. © Horizon Therapeutics, LLC. All rights reserved. Jackson's Lemon Linctus (Glycerol) is a registered trademark of Horizon Therapeutics, LLC. For more information, go to www. RAVICTI.com or call 1-855-823-7878. | ||
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WARNINGS
This product is intended for use only by licensed medical personnel experienced in administering allergenic extracts and trained to provide immediate emergency treatment in the event of a life-threatening reaction.
Hymenoptera Venom extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death.(1) Therefore, emergency measures and personnel trained in their use must be available immediately in the event of such a reaction. Patients should be instructed to recognize adverse reaction symptoms, observed in the office for at least 30 minutes after skin testing or treatment, and cautioned to contact the physician's office if symptoms occur. See ADVERSE REACTION, Section 4, of this instruction for information regarding adverse event reporting.
All patients should have available an Emergency Anaphylaxis Kit containing epinephrine and be instructed in its use for emergency treatment of possible systemic reactions occurring at times after the patient has departed the testing or treatment premises. Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.(1)
Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.(2)
Immunotherapy for insect sting allergy should be given to those patients who have experienced significant systemic reactions (for detailed description of symptoms see INDICATIONS AND USAGE and ADVERSE REACTIONS) from insect stings and who demonstrate hypersensitivity by skin testing with these products. The only approved method for diagnosing insect sting allergic patients for immunization is by skin testing.
This product must never be injected intravenously.
Refer also to CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS and OVERDOSAGE for further discussion.
DESCRIPTION
Hymenoptera Venom Products available are sterile freeze-dried venom of Jackson's Lemon Linctus (Honey) Bee (Apis mellifera) and venom protein of Yellow Jacket (Vespula sp.), Yellow Hornet (Dolichovespula arenaria), White-Faced Hornet (Dolichovespula maculata) and Wasp (Polistes sp.). Mixed Vespid venom protein (Yellow Jacket, Yellow Hornet and White-Faced Hornet) is also available.
The reconstituted single venom products are intended for subcutaneous injection for immunotherapy and percutaneous use for diagnosis. The Mixed Vespid venom protein is for immunotherapy only, not for diagnosis. Diagnosis should be based on individual venoms.
Because of the difficulty in collecting all species of Yellow Jacket and Wasp, the venom raw materials for these two insects may vary in species composition from lot to lot. A listing of the exact species content for any particular lot of Yellow Jacket or Wasp venom protein may be obtained by calling Technical Services at Jubilant HollisterStier, (800) 992-1120.
Final containers of sterile freeze-dried venom products are sealed under vacuum. This will result in the diluting fluid being forcibly drawn into the sealed vial when the syringe needle penetrates the seal during reconstitution. See PRECAUTIONS.
Venom or venom protein is supplied in 2 mL diagnostic vials and in 2 mL vials for treatment maintenance. The chart below lists for each vial size the content of lyophilized venom or venom protein and reconstituted product, (mannitol and venom concentrations). Trace amounts of sodium chloride, potassium chloride, acetic acid and beta-alanine, as well as the constituents of the reconstituting fluid, will also be present.
| | Vial Size | µg Venom or Venom Protein | Reconstitution | mg/mL Mannitol | Venom Concentration |
| Single Venom | 2 mL | 120 | 1.2 mL | 7.7 mg/mL | 100µg/mL |
| Mixed Vespid | 2 mL | 360 | 1.2 mL | 23.1 mg/mL | 300 µg/mL |
Maintenance sterile freeze-dried products can be reconstituted in Sterile Albumin Saline with Phenol (which contains 0.9% NaCl, 0.4% phenol and 0.03% Human Serum Albumin) to a concentration of 100 µg/mL (300 µg/mL for Mixed Vespid venom protein). The diagnostic product should be reconstituted only with Sterile Albumin Saline with Phenol (0.4%). See DOSAGE AND ADMINISTRATION for details of dilutions for diagnosis and treatment.
Space is provided on the container label to record the date (month, day, year) venom is reconstituted. Refer to dating period shown under PRECAUTIONS. At the time of reconstitution, write the calculated reconstituted product expiration date (month, day, year) on the vial label in the space provided.
CLINICAL PHARMACOLOGY
DiagnosisDiluted solutions of stinging insect venom injected intradermally will produce wheal and erythema reactions in patients who have significant IgE-mediated, Type I immediate hypersensitivity to stings of these insects.
Treatment
Repeated injections of increasing doses of insect venom extracts have been shown to ameliorate the intensity of allergic symptoms upon subsequent insect stings.(3, 4)
The mechanism by which hyposensitization is achieved is not known completely. IgG antibodies (blocking antibodies) appear in the serum of patients treated with injected venom. No direct relationship has been identified between the level of blocking antibody (or the ratio of blocking antibody to IgE antibody directed to the same venom antigens) and the degree of hyposensitization. However, patients who show protection from symptoms after stings have been found to have significant levels of specific blocking antibody.(3, 4)
Initially, after a period of immunotherapy with specific venom antigens, levels of IgE antibody may increase.(4)However, from studies carried out with other venom preparations, these levels are reported to decline after a time.(5) After maintenance level has been reached and maintained, symptoms after stings have been shown to decrease considerably.(3, 4)
It is not known if skin-sensitizing antibody can be eradicated or if the patient can be entirely cured, nor is it known how long immunotherapy must be continued.
In a clinical study with Jubilant HollisterStier venom products, injections (using the Suggested Dose Schedule under DOSAGE AND ADMINISTRATION) were given once per week at one study center, and twice or more per week at another center.(4) (For further discussion, see below). It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom.
In the clinical trial, 97% of patients at the maintenance dosage (100 µg per venom) showed no systemic reaction following an insect sting challenge.(4)The remaining 3% had a milder reaction than noted prior to treatment. The patients in this study reached maintenance (100 µg per venom) usually within 2 1/2 -3 1/2 months after beginning therapy.(4)Whether efficacy of therapy is influenced by the time required to reach maintenance has not yet been determined.
Large local reactions occurred in approximately 60% of the patients given immunotherapy. Some form of systemic response occurred, often repeatedly, in one-third of the patients treated in the clinical trial.(4)Only one systemic response occurred on the first dose given. The rest occurred at various times in the course of immunotherapy. Some systemic manifestations may have occurred because of the patient's apprehension, and did not require treatment. Approximately one-fourth of the patients experiencing systemic responses were given some form of specific therapy (epinephrine, theophylline, or metaproteranol), some on several occasions.(4)
In deciding the criteria for proceeding from dose to dose of the Suggested Dose Schedule, the results of the clinical study (4)should be considered. A study center "A" reporting the least number of systemic reactions during pre-maintenance treatment held the dose constant in most of the cases where significant local reactions occurred. With the systemic reactions reported, this center held the dose the same in approximately 80% of the incidences. The treatment injections were given at this center usually once per week, and if a patient missed an appointment, the next dose was often the same as the preceding dose (depending on the previous reactivity of the patient). Patients treated at this center reached maintenance in an average of 17-19 visits. Another study center "B", reporting a higher incidence of systemic reactions, was more regimented in following the Suggested Dose Schedule. This center reduced or held the dose the same in less than 10% of the cases reporting significant local reactions. With the systemic reactions reported, this center held the dose the same or reduced the dosage in approximately 20% of the cases. At this center, more than one injection per week was given at the outset as circumstances and sensitivity allowed. Patients treated at this center reached maintenance in an average of 14 visits.
Following the achievement of maintenance level (100 µg per venom), approximately 80% or more patients were given a second maintenance injection at a 1-week interval. The third maintenance injection was usually (in approximately 60% of the patients) at a 2-week interval. The next injection was usually within 3 weeks, and thereafter, the patients were injected for ongoing maintenance at approximately monthly intervals.(4)
INDICATIONS AND USAGE
Insect stings may induce a wide range of allergic symptoms in sensitive patients. A normal sting response is initial burning or stinging pain that may be intense and last several minutes to an hour or more. There is usually some local swelling coming on immediately and persisting for several days. The location of the sting has considerable influence on the intensity of the pain and extent of swelling. Stings on the fingers or feet produce much pain, but less swelling; whereas a sting on the head or face produces extensive swelling with variable pain.
Local reactions coming on rapidly and larger than the usual local reaction, particularly if the swelling spans both adjacent joints on the extremities, can indicate hypersensitivity. Systemic symptoms come on shortly after the sting, often within seconds to minutes. Symptoms may range from generalized flushing, itching, redness, diffuse swelling of the skin or urticarial wheals, abdominal cramps, nausea, vomiting, or incontinence of urine or stool, to faintness, blurring or loss of vision, unconsciousness, seizures, respiratory or cardiac arrest, or death. Later reactions may consist of fever, achiness, malaise, joint swelling, urticaria or other signs of vascular damage typical of serum sickness, a Type III reaction. Typical delayed Type IV reactions may also occur.(6) Rarely, other types of severe reactions to insect stings have been reported.(6)These include serum sickness, hematologic abnormalities, and neurological disorders commencing some time after a sting, and not associated with anaphylactoid reactions. These patients are not candidates for immunotherapy using insect venoms.
(1) Diagnosis
Skin testing with insect venoms is useful to demonstrate the presence of IgE antibodies which account for the patient's symptoms.(3)Patients are seldom able to identify the insect which stung them, so skin testing is used to determine the insect culprit. Dilutions of these venom products will help judge the sensitivity of the patient and whether the patient should be treated.(7)
It is not absolutely known what levels (micrograms) of venom, that elicit positive skin tests, are diagnostic of clinical sensitivity. However, patients with a history of reactions (any of three types: generalized urticaria or angioedema; respiratory difficulty due either to laryngeal edema or to bronchospasm; or vascular collapse, with or without loss of consciousness) to previous stings and a positive skin test to a venom intradermal injection of approximately 1 µg/mL had about a 60% chance of reacting again when stung by the same insect. These patients should receive venom immunotherapy.(3)
Patients with a history of reaction (any of the three reaction types described above) to previous stings, but who did not demonstrate a positive skin test reaction to venom, were considered in a previous study not to be clinically sensitive, and were not treated.(3) We cannot recommend treatment for such patients.
Another study demonstrated false positive reactions when skin testing with venom concentrations of 10 µg/mL and 100 µg/mL was carried out.(8) Thus there can be a nonspecific skin test reaction potentially due to the pharmacological action of the venom at higher concentrations.
The best statement that can be made, at present, is that patients with significant positive history (reactions of the three types described above) following an insect sting, and who do react with a positive skin test to a venom concentration of 1 µg/mL or less, are recommended for treatment. Patients who have the history described above, but who do not react to a 1 µg/mL intradermal venom skin test, cannot be recommended for treatment. At present, the data does not exist, to determine whether a patient who might react to a higher concentration, e.g., 2-10 µg/mL, is at risk from a subsequent sting or not. Since it is not known if sting-sensitive patients who subsequently lose their IgE anti-venom antibody can be resensitized by further stings, it is advisable to retest these patients after any subsequent stings.(3) However, since the level of venom-specific IgE may fall to low levels briefly after a sting, patients should not be re-tested until 2 to 4 weeks after any sting.
(2) Treatment
Immunotherapy is indicated for those patients diagnosed as sensitive and is accomplished by using graduated dilutions of the appropriate insect venom or venoms to control the severity of the patient's symptoms from subsequent stings.
Increasing doses of venom are given at intervals, dependent on the patient's ability to tolerate the venoms, until a maintenance dosage (100 µg per venom is recommended - 300 µg in the case of the Mixed Vespid venom protein) is reached and maintained.
Venom sensitivity differs for individual patients, thus it is not possible to provide a dosage schedule that is universally suited to all patients. The dosage schedule shown under DOSAGE AND ADMINISTRATION is a summary of the schedule used in clinical trials of our product and found suitable for the majority of patients.
In highly sensitive patients, the physician may be required to use a modified dose schedule, based on the patient's sensitivity to and tolerance of the injections. Lower initial doses and smaller dosage increments than shown under DOSAGE AND ADMINISTRATION may be necessary.
CONTRAINDICATIONS
There are no known absolute contraindications to immunotherapy using Hymenoptera Venom Products. See also PRECAUTIONS and WARNINGS.
Patients showing negative intradermal skin tests to specific venoms at 1 µg/mL are not recommended for venom treatment.
Any injections, including immunotherapy, should be avoided in patients with a bleeding tendency. Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.(1)
Patients on beta blockers may be more reactive to allergens given for testing or treatment and maybe unresponsive to the usual doses of epinephrine used to treat systemic reactions.(2)
Since there are differences of opinion concerning the possibility of routine immunizations exacerbating autoimmune diseases, immunotherapy should be given cautiously to patients with other immunologic diseases and only if the risk from insect stings is greater than the risk of exacerbating the underlying disorder.
WARNINGS
See WARNINGS box at the beginning of this Instruction Sheet. See also PRECAUTIONS.Venom extract must be temporarily withheld from patients or the dose adjusted downward if any of the following conditions exist: (1) severe symptoms of rhinitis and/or asthma; (2) infection or flu accompanied by fever; (3) any evidence of an excessively large local or any generalized reaction during the initial stages of immunotherapy, or during maintenance therapy; and/or (4) insect sting prior to a scheduled injection. Do not administer venom injections during a period of symptoms following an insect sting or on the day the patient received an insect sting, since this could result in an allergen load that exceeds the patient's tolerance.
THE CONCENTRATE MUST NOT BE INJECTED AT ANY TIME UNLESS TOLERANCE HAS BEEN ESTABLISHED. DILUTE CONCENTRATED EXTRACTS WITH STERILE ALBUMIN SALINE WITH PHENOL (0.4%) FOR SKIN TESTING AND IMMUNOTHERAPY.
INJECTIONS MUST NEVER BE GIVEN INTRA VENOUSLY. Subcutaneous injection is recommended. Intracutaneous or intramuscular injections may produce large local reactions or be excessively painful. AFTER INSERTING NEEDLE SUBCUTANEOUSLY, BUT BEFORE INJECTING, ALWAYS WITHDRAW THE PLUNGER SLIGHTLY. IF BLOOD APPEARS IN THE SYRINGE, CHANGE NEEDLE AND GIVE THE INJECTION IN ANOTHER SITE.
Patients with hypersensitivity to insect venom who undergo desensitization treatment while under concomitant therapy with ACE (angiotensin-converting enzyme) inhibitors, may have an increased risk of life-threatening anaphylactic reactions.(9) Patients without insect venom hypersensitivity, who take ACE inhibitors, and are stung by insects such as bee or wasp can show such reactions as well.(10)
Two patients undergoing desensitization treatment with Hymenoptera Venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.(11) IF CHANGING TO A DIFFERENT LOT OR A FRESHLY RECONSTITUTED VIAL OF VENOM EXTRACT:
All extracts lose potency over time, and a fresh extract could have an effective potency that is substantially greater than that of the old extract. The first dose from the new vial should not exceed 50% of the previous dose.
IF THE VENOM EXTRACT PREVIOUSLY USED WAS FROM ANOTHER MANUFACTURER: Since manufacturing processes and sources of raw materials differ among manufacturers, the interchangeability of extracts from different manufacturers cannot be insured. The starting dose of the venom extract therefore should be greatly decreased even though the extract is the same formula and dilution. In general, a dose reduction to 50% of the previous product dose should be adequate, but each situation must be evaluated separately considering the patient's history of sensitivity, tolerance of previous injections, and other factors. If the patient tolerates a 50% decrease, the next dose could be raised to the previous dose amount. If the decrease is greater than 50%, the next dose would need to be determined by the allergist, depending on the situation. Dose intervals should not exceed one week when rebuilding dose. See DOSAGE AND ADMINISTRATION.
IF A PROLONGED PERIOD OF TIME HAS ELAPSED SINCE THE LAST INJECTION: Patients may lose tolerance for allergen injections during prolonged periods between doses. The duration of tolerance is an individual characteristic and varies from patient to patient. In general, the longer the lapse in the injection schedule, the greater dose reduction required. If the interval since last dose is over four weeks, perform skin tests to determine starting dose. See DOSAGE AND ADMINISTRATION.
IF THE PREVIOUS EXTRACT WAS OUTDATED: The dating period for allergenic extracts indicates the time that they can be expected to remain potent under refrigerated storage conditions (2° - 8°C). During the storage of extracts, even under ideal conditions, some loss of potency occurs. For this reason, extracts should not be used beyond their expiration date. If a patient has been receiving injections of an outdated extract, s/he may experience excessive local or systemic reactions when changed to a new, and possibly more potent extract. In general, the longer the material has been outdated, the greater the dose reduction necessary when starting the fresh extract. Proper selection of the dose and careful injection should prevent most systemic reactions. It must be remembered, however, that allergenic extracts are highly potent in sensitive individuals and that systemic reactions of varying degrees of severity may occur, ranging from mild to life-threatening anaphylaxis, or even death, as described under INDICATIONS AND USAGE and ADVERSE REACTIONS. Patients should be informed of this, and the warnings and precautions should be discussed prior to immunotherapy. See PRECAUTIONS below. Systemic reactions should be treated as indicated in ADVERSE REACTIONS.
PRECAUTIONS
1. GENERAL
The presence of asthmatic signs and symptoms appear to be an indicator for severe reactions following allergy injections. An assessment of airway obstruction either by measurement of peak flow or an alternate procedure may provide a useful indicator as to the advisability of administering an allergy injection.
Concentrated extracts must not be injected unless tolerance has been established.
Diluting fluid should be forcibly drawn into the sealed vial when the syringe needle penetrates the seal during reconstitution. Failure of this to occur for a particular vial indicates possible loss of vacuum. Vials without vacuum should be returned to the manufacturer.
Record date of reconstitution and expiration date of reconstituted product in the space provided on the product label. Date of expiration after reconstitution must not exceed the Final Expiration Date indicated on the container label..
Store freeze-dried and reconstituted venom product, stock solutions and venom dilutions constantly at 2 - 8 C.
| Venom Concentration | Diluent | Recommended Expiration Date* |
| 100 µg/mL | Albumin Saline with Phenol (0.4%) | 6 Months |
| 10µg/mL | Albumin Saline with Phenol (0.4%) | 1 month |
| 1 µg/mL | Albumin Saline with Phenol (0.4%) | 1 month |
| 0.1 µg/mL | Albumin Saline with Phenol (0.4%) | 14 days |
| Less than 0.1 µg/mL | Albumin Saline with Phenol (0.4%) | Prepare fresh daily |
*But not to exceed Final Expiration Date indicated on the container label.
Sterile solutions, vials, syringes, etc., should be used and aseptic precautions observed in making dilutions.
To avoid cross-contamination, do not use the same needle to withdraw materials from vials of more than one extract, or extract followed by diluent.
A sterile tuberculin syringe, with a needle at least 5/8" long and graduated in 0.01 mL units, should be used to measure carefully each dose from the appropriate dilution. Aseptic techniques should always be employed when injections are being administered.
A separate sterile syringe should be used for each patient to prevent transmission of hepatitis and other infectious agents from one person to another.
Patient reactions to previous injections should be reviewed before each new injection so that dose can be adjusted accordingly. See ADVERSE REACTIONS and WARNINGS.
Rarely, a patient is encountered who develops systemic reactions to minute doses of allergen and does not demonstrate increasing tolerance to injections after several months of treatment. It is suggested that if systemic reactions or excessive local responses occur persistently at very small doses, efforts at immunotherapy should be stopped.
PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER SKIN TESTING AND AFTER EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for such treatment measures.
2. INFORMATION FOR PATIENTS
Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock.. Patients should be made to understand the importance of a 30 minute observation period following skin testing or therapeutic injections, and be cautioned to return to the office promptly if symptoms occur after leaving. Patients should be instructed in the use of, and have available, an Emergency Anaphylaxis Kit for self-administration of epinephrine.
Patients must be instructed to report any insect stings that have occurred, since a venom injection should not be given on the same day as the sting, nor during a time when the patient is still experiencing symptoms from the sting.
3. DRUG INTERACTIONS
Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic, unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.
Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
See WARNINGS section regarding concurrent treatment with ACE inhibitors.
Certain medications may lessen the skin test wheal and erythema responses elicited by allergens and histamine for varying time periods. Conventional antihistamines should be discontinued at least 5 days before skin testing. Long acting antihistamines should be discontinued for at least 3 weeks prior to skin testing.(17) Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.(17, 18)
Tricyclic antidepressants such as doxepin, should be withheld for at least 7 days before skin testing.(19) Topical local anesthetics may suppress the flare responses and should be avoided on skin test sites.(20)
When using other drugs in patients receiving allergenic extracts, always consult the product labeling of the other drugs to determine any possible interaction with use of allergenic extracts, and specifically with stinging insect (Hymenoptera) venom extracts.
4. CARCINOGENESIS AND MUTAGENSIS AND IMPAIRMENT OF FERTILITY
Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity, or impairment of fertility.
5. PREGNANCY
Pregnancy Category C. Animal reproduction studies have not been conducted with Hymenoptera Venom Products. It is also not known whether Hymenoptera Venom Products can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Hymenoptera Venom Products should be given to a pregnant woman only if clearly needed.
On the basis of histamine's known ability to contract uterine muscle, theoretically, a systemic reaction, whether occurring from insect sting or from venom skin testing or treatment dose, should be avoided. Therefore, the physician must carefully consider the benefit-to-risk ratio, to both patient and fetus, of continuing venom immunotherapy during pregnancy, or performing venom skin testing, and especially of initiating a venom immunotherapy program where there is a possibility that the patient may not be able to reach the recommended maintenance dose without significant risk of a systemic reaction.
6. NURSING MOTHERS
There are no current studies on secretion of the allergenic extract components in human milk or effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.
7. PEDIATRIC USE
Since dosage for the pediatric population is the same as for adults, the larger volumes of solution may produce excessive discomfort. Therefore, in order to achieve the total dose required, the volume of the dose may need to be divided into more than one injection per visit. A study done in children ages 4 to 17 showed no special problems with venom immunotherapy in this population.
8. GERIATRIC USE
The reactions from immunotherapy can be expected to be the same in elderly patients as in younger ones. Elderly patients may be more likely to be on medication that could block the effect of epinephrine which could be used to treat serious reactions, or they could be more sensitive to the cardiovascular side effect of epinephrine because of pre-existing cardiovascular disease.(23)
ADVERSE REACTIONS
Physicians administering Hymenoptera Venom testing or treatment materials should be experienced in the treatment of severe systemic reactions.(1) Local Reactions
Some erythema, swelling or pruritis at the site of injection are common, the extent varying with the patient. Excessively large, painful or persistent local reactions can occur from skin tests or immunotherapy. Frequent application of cold, wet dressings to the area and/or the use of oral antihistamines will ameliorate the discomfort. Reactions usually subside in 24-36 hours. Large local reactions occurred in approximately 60% of the patients given immunotherapy in a clinical study. None of the local reactions required specific treatment; however, subsequent injections in many instances were held to the previous dose or a reduced dose. Some patients had repeated large local reactions that slowed the increase in the immunotherapy dose.4
See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION Sections.
A mild burning immediately after the injection is to be expected. This usually leaves in 10 to 20 seconds. See also WARNINGS and PRECAUTIONS regarding proper method and route of injection.
(2) Systemic Reactions
Most severe systemic reactions will begin within a 30 minute time period, but systemic reactions may occur at any time after skin tests or immunotherapy. Symptoms may range from mild to life threatening from anaphylaxis as described under INDICATIONS AND USAGE.
With careful attention to dosage and administration, severe systemic reactions occur infrequently, but it cannot be overemphasized that in sensitive individuals, any injection could result in anaphylactic shock. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions. See CLINICAL PHARMACOLOGY for clinical incidence of systemic reactions and course of action following these reactions.
If a systemic or anaphylactic reaction does occur, inject 1:1000 epinephrine-hydrochloride intramuscularly or subcutaneously.
EPINEPHRINE DOSAGE
ADULT: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.
PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient.
After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and possibly vasoactive drugs. Airway patency should be insured. Oxygen should be given by mask. Intravenous antihistamines, inhaled bronchodilators, theophylline and/or corticosteroids may be used if necessary after adequate epinephrine and circulatory support have been given.
Emergency resuscitation measures and personnel trained in their use must be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures [Ref. J. Allergy and Clinical Immunology, 77(2): p.271-273, 1986]. Rarely are all of the above measures necessary; epinephrine usually produces a prompt response. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance. For recommendations regarding how to proceed with venom extract dose following systemic reactions, see WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION.
3. Adverse Event Reporting
Report all adverse events to Jubilant HollisterStier LLC Customer Technical Services Department at 1(800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1(800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1(800) FDA-0178.
OVERDOSAGE
See ADVERSE REACTIONS Section.
DOSAGE AND ADMINISTRATION
General
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Reconstitute and dilute the freeze-dried venom as directed below. Sterile Albumin Saline with Phenol (0.4%) must be used to reconstitute and dilute the venoms for skin testing and treatment.
Reconstitute the freeze-dried venoms by adding 1.2 mL Sterile Albumin Saline with Phenol (0.4%) to the vial using a sterile syringe. Swirl or rock the container to dissolve the venom completely. DO NOT SHAKE, since shaking can cause foaming.
Dilutions must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solutions, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Maintain stock solutions and dilutions constantly at 2° - 8°C.
| Extract of Volume | Extract Concentration | | Diluent Volume | | Dilution Concentration |
| 1 part of | 100 µg/mL | + | 9 parts | = | 10 µg/mL |
| 1 part of | 10 µg/mL | + | 9 parts | = | 1 µg/mL |
| 1 part of | 1µg/mL | + | 9 parts | = | 0.1µg/mL |
| 1 part of | 0.1 µg/mL | + | 9 parts | = | 0.01 µg/mL |
| 1 part of | 0.01 µg/mL | + | 9 parts | = | 0.001 µg/mL |
| 1 part of | 0.001 µg/mL | + | 9 parts | = | 0.0001 µg/mL |
| Extract of Volume | Extract Concentration | | Diluent Volume | | Dilution Concentration |
| 0.2mL of | 100 µg/mL | + | 1.8mL | = | 10 µg/mL |
| 0.2mL of | 10 µg/mL | + | 1.8mL | = | 1 µg/mL |
| 0.2mL of | 1 µg/mL | + | 1.8mL | = | 0.1 µg/mL |
| 0.2mL of | 0.1 µg/mL | + | 1.8mL | = | 0.01 µg/mL |
| 0.2mL of | 0.01 µg/mL | + | 1.8mL | = | 0.001 µg/mL |
| 0.2mL of | 0.001 µg/mL | + | 1.8mL | = | 0.0001 µg/mL |
USE OF VENOMIL DIAGNOSTIC SETS
The Venomil Diagnostic Sets from Jubilant HollisterStier contain a vial of freeze dried venom protein that when reconstituted as instructed below will contain 100 µg venom or venom protein/mL.
To use the Venomil Diagnostic set, follow these steps:
1. Open box and remove contents. Be sure to read the complete package Instruction Sheet paying particular attention to the WARNINGS, PRECAUTIONS, CONTRAINDICATIONS, and ADVERSE REACTIONS.
2. Remove the freeze-dried venom vial and one of the seven vials of diluent from the kit. Withdraw 1.3 mL of Albumin Saline with Phenol (0.4%) from the diluent vial using a 2 or 3 mL disposable syringe. Expel some Albumin Saline with Phenol (0.4%) from the syringe until exactly 1.2 mL are remaining in the syringe. The remaining Albumin Saline with Phenol (0.4%) in the diluent vial may be marked "Control" and used as a negative control for prick testing.
3. Insert the needle of the diluent syringe into the vial of venom and expel the diluent. Remove the syringe. Swirl or rock the vial to dissolve the venom completely. DO NOT SHAKE. Shaking can cause foaming of the extract.
At this point, you have completed the reconstitution of the freeze-dried venom. The reconstituted products contain 100 µg of venom or venom protein per mL. DO NOT USE THIS STRENGTH FOR INTRADERMAL SKIN TESTING. DISCARD AFTER THE DILUTIONS HAVE BEEN PREPARED.
4. Remove six vial labels from the kit and mark them: 10 µg/mL, 1 µg/mL, 0.1 µg/mL, 0.01 µg/mL, 0.001 µg/mL and 0.0001 µg/mL. Withdraw 0.2 mL of venom extract in a 1 mL syringe from the vial reconstituted in step #3. Insert the syringe needle into one vial of 1.8 mL Albumin Saline with Phenol (0.4%). Slowly expel the 0.2 mL venom into it. Swirl or rock to mix, and label 10 µg/mL.
5. Withdraw 0.2 mL of the 10 µg/mL venom extract and inject into another vial of 1.8 mL Albumin Saline with Phenol (0.4%). Mix and label 1 µg/mL.
6. The four additional dilutions should be prepared in the same manner.
(2) Diagnosis
Since the level of insect venom specific IgE may fall to low levels briefly after a reaction to a sting, patients should not be tested until 2 to 4 weeks after any sting. Skin testing should be carried out with all five individual venoms, since many patients have multiple sensitivities.(4) Mixed Vespid venom protein should be used only for therapy - not for diagnosis.
Prick testing should be done before intradermal testing to determine appropriate concentration for intradermal testing. See Intradermal Tests. Skin testing (prick and intradermal) provides information to assist in identifying those patients who are to be classified as extremely sensitive and who may not tolerate the Suggested Dose Schedule. See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION.
In both the prick and intradermal tests, a negative control test with diluent alone must be performed. A histamine positive control test is also recommended.
The flexor surface of the forearm is the usual location for skin testing. It is important that a separate sterile syringe and needle be used for each extract and each patient.
Prick Tests: Prick tests are accomplished by applying one drop of the 1 µg/mL venom extract to the forearm, and by pricking the skin through the surface of the drop with a sterile 27 gauge needle. The prick is superficial and should not draw blood.
Skin response should be assessed after approximately 15-20 minutes.
For prick tests, a positive reaction (reaction greater than diluent control) at the 1 µg/mL concentration indicates a high level of sensitivity to the test venom.
Intradermal Tests: Patients showing a positive reaction to the prick test at the 1 µg/mL concentration should begin intradermal tests at concentrations of not more than 0.0001 to 0.001 µg/mL. Patients with negative prick tests may begin intradermal tests at a concentration of 0.001 µg/mL.
A 1 mL tuberculin syringe with a short 27-gauge needle should be used to deliver a volume of 0.05 mL for intradermal testing. Introduce the needle into the superficial skin layers, bevel down, until the bevel is completely buried, then slowly inject a 0.05 mL aliquot of the venom dilution, making a small bleb.
Start intradermal tests with the most dilute solution. If after 20 minutes no skin reaction is obtained, continue the intradermal testing using ten-fold increments in the concentration until a reaction of 5-10 mm wheal and 11-20 mm erythema is obtained, or until a concentration of 1 µg/mL has been tested, whichever occurs first.
A patient should be considered sensitive to the test venom when a skin response of 5-10 mm wheal and 11-20 mm erythema (or greater) occurs at a concentration of 1 µg/mL or less,(8)providing that this reaction is greater than that of the diluent control.
(3) Immunotherapy
For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.
The most common site of injection is the lateral aspect of the upper arm.
Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms). Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions.
CAUTION: Sensitivity to venom differs from patient to patient. Thus, it is not possible to provide a dosage schedule suitable for all patients. The Suggested Dose Schedule shown below was used in
clinical trials(4)and should be suitable for a majority of patients.
IN EXTREMELY SENSITIVE PATIENTS, however, an individualized dose schedule must be employed which will be dictated by the patient's sensitivity. This individualized schedule will probably include weaker dilutions and smaller increments between doses in progressing to the maintenance level (100 µg per venom).
In identifying those patients to be classified as extremely sensitive, individuals reacting with significant skin test (wheal greater than 5 mm and erythema greater than 20 mm) at intradermal skin test concentrations of 0.01 µg/mL or less, or those patients experiencing a systemic reaction to any venom skin test concentration, should be considered highly sensitive.
Suggested Dose Schedule for a Single Venom:
| Dose No. | *Volume of 1 µg/mL | Dose No. | Volume of 10 µg/mL | Dose No. | Volume of 100 µg/mL |
| 1... | ...0.05 mL | 5... | ...0.05 mL | 9... | ...0.05mL |
| 2... | ...0.10 mL | 6... | ...0.10 mL | 10... | ...0.10mL |
| 3... | ...0.20 mL | 7... | ...0.20 mL | 11... | ...0.20mL |
| 4... | ...0.40 mL | 8... | ...0.40 mL | 12... | ...0.40mL |
| 13... | ...0.60mL | ||||
| 14... | ...0.80mL | ||||
| 15... | ...1.00mL |
Mixed Vespid Venom will contain three times the venom protein per mL shown in this table.
*See preceding CAUTION Section.
ALTERNATE MAINTENANCE DOSE SCHEDULE
If the above suggested dosage schedule has been followed, Dose #15 will have emptied the third vial of venom. There should now be three vials of freeze-dried venom remaining in the maintenance set. If a smaller volume maintenance dose is desired, then the remaining vials of venom may be reconstituted with 0.6 mL of Sterile Albumin Saline with Phenol (0.4%) instead of the previously recommended 1.2 mL. When 0.6 mL is used for reconstitution, the maintenance dose volume then becomes 0.5 mL instead of 1.0 mL. The 0.5 mL injection will still contain 100 micrograms of venom or venom protein.
Precautions should be taken to ensure that maintenance level injections of 0.5 mL are given only from those vials of venom that have been reconstituted with 0.6 mL of diluting fluid. Any other volume used for reconstitution will not give 100 micrograms of venom or venom protein at a dosage of 0.5 mL In proceeding with the Suggested Dose Schedule, or modified schedules (for highly sensitive patients) it is recommended that injections be given at least once per week, as in the clinical studies.. When building the dose, it is important that dose intervals not exceed one week since longer intervals may decrease the patient's tolerance of the extract.
Based on the clinical studies (4)it is suggested that if a systemic, extremely large local (10 cm or more in duration, or other severe local symptoms), or persistent and severe delayed local reaction occurs during the dose building phase, the dose at the next visit be held constant (or reduced, depending on judgment of the severity of the reaction) as was done at Study Center "A," which reported the least number of systemic reactions during the course of therapy.
It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom. Following the achievement of maintenance level (100 µg per venom), it is recommended that a second maintenance injection be given at a 1-week interval, and a third maintenance injection at a 2-week interval. Administer the next injection at a 3-week interval, and then monthly for ongoing maintenance.
See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE for further information regarding clinical studies on which the above recommendations are based.
The optimum duration for immunotherapy is not known, so current recommendations are that maintenance injections be continued indefinitely, year around, particularly in patients experiencing life-threatening anaphylaxis after insect stings.
PEDIATRIC USE
The dose for the pediatric population is the same as for adults..
GERIATRIC USE
The dose for elderly patients is the same as for adult patients under 65.(23).
HOW SUPPLIED
Jubilant HollisterStier LLC sterile freeze-dried Hymenoptera Venom Products are supplied in vacuum-sealed vials containing venom extract with mannitol as an excipient.. Reconstituting fluid [Sterile Albumin Saline with Phenol (0.4%)] is supplied with the Venomil® kit, and is also available separately.
Storage:
Store freeze-dried and reconstituted venom product, and venom dilutions, at 2° - 8° C, and keep at this temperature range during office use.
LIMITED WARRANTY
A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.
REFERENCES
1. Lockey, Richard F., Linda M. Benedict, Paul C. Turkeltaub, Samuel C. Bukantz. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol. 79 (4): 660-677, 1987.
2. Jacobs, Robert L., Goeffrey W. Rake, Jr., et. al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J. Allergy Clin. Immunol. 68 (2): 125-127, August 1981.
3. Hunt, K. J., M. D. Valentine, A. K. Sobotka, A. W. Benton, F. J. Amodio, L. M. Lichtenstein. A controlled trial of immunotherapy in insect hypersensitivity. New Eng. J. Med. 299: 157-161, July 27, 1978.
4. Summary of data from BB-IND 1292 clinical studies, 1978-79, on Hollister-Stier products.
5. Amodio, F., L. Markley, M. D. Valentine, A. K. Sobotka, L. M. Lichtenstein. Maintenance immunotherapy for Hymenoptera sensitivity. J. Allergy Clin. Immunol. 61 (3): 134, 1978.
6. Reisman, R. E., Allergy Principles and Practice. E. Middleton, C. E. Reed, E. F. Ellis, ed. C. V. Mosby Co., 1978.
7. Sobotka, A. K., N. F. Adkinson, Jr., M. D. Valentine, L. M. Lichtenstein. Allergy to insect stings. IV. Diagnosis by R.A.S.T. J. Immunol. 121 (6): 2477-2484, 1978.
8. Hunt, K. J., M. D. Valentine, A. K. Sobotka, L. M. Lichtenstein. Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms. Annals Int. Med. 85: 56-59, 1976.
9. Annals of Allergy, Asthma and Immunology. Inhibitors of angiotensin II: Potential hazards for patients at risk for anaphylaxis. Editorial. 78: 527-529, June 1997.
10. Pharm. Ind. (Germany). Anaphylactoid reactions in patients treated with ACE inhibitor treatment in combination with desensitization treatment or after insect bites. 56 (9): IX226-227, 1994.
11. Tunon-De-Lara, J. M., et al. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. The Lancet (United Kingdom). 340 (8824): 908, Oct. 10, 1992.
12. Weinstien, A. M., B. D. Dubin, W. K. Podleski, S. L. Spector, R. S. Farr. Asthma and pregnancy. JAMA. 124 (11): 1161-1165, 1979.
13. Reid, M. J., R. F. Lockey, P. C. Turkletaub, T. A. E. Platts-Mills. Survey of fatalities from skin testing and immunotherapy. J. Allergy Clin. Immunol. 92 (1): 6-15, July 1993.
14. Reid, M. J., G. Gurka. Deaths associated with skin testing and immunotherapy. J. Allergy Clin. Immunol. 97 (1) Part 3:231, Abstract 195, January 1996.
15. Thompson, R. A. et al. Report of a WHO/IUIS working group. The current status of allergen immunotherapy (hyposensitization). Allergy. 44: 369-379, 1989.
16. Malling, H.J., B. Weeke, et al. The European Academy of Allergology and Clinical Immunology. Position Papers. Allergy. 48 (Supplement 14): 9-82, 1993.
17. Pipkorn, Ulf. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86, 1988.
18. Andersson, M. U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. J. Allergy Clin. Immunol. 79 (2): 345-349, February 1987.
19. Rao, Kamineni S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. J. Allergy Clin. Immunol. 82: 752-757, November 1988.
20. Pipkorn, Ulf, M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clinical Allergy. 17: 307-311, 1987.
21. DuBuske, L. M., C. J. Ling, A. L. Sheffer. Special problems regarding allergy immunotherapy. Immunol. Allergy Clin. North Am. (USA). 12 (1): 145-175, 1992.
22. Graft, D., K. Schuberth, A. Kagey-Sobotka, K. Kwiterovich, Y. Niv, L. Lichtenstein, M. Valentine. Assessment of prolonged venom immunotherapy in children. J. Allergy Clin. Immunol. 80 (2): 162-169, August 1987.
23. Peebles, Ray Stokes, Jr., B. Bochner, Howard J. Zeitz, ed. Anaphylaxis in the elderly. Immunol. Allergy Clin. of North Am. 13 (3): 627-646, August 1993.
Suggested Dosage Table
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- Dailymed."AMINO ACIDS; CALCIUM ACETATE; GLYCERIN; MAGNESIUM ACETATE; PHOSPHORIC ACID; POTASSIUM CHLORIDE; SODIUM ACETATE; SODIUM CHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- "glycerol". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
- "glycerol". http://www.drugbank.ca/drugs/DB0946... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Jackson's Lemon Linctus?Depending on the reaction of the Jackson's Lemon Linctus after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Jackson's Lemon Linctus not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Jackson's Lemon Linctus addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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