Fast Facts: Lopinavir and Ritonavir (40 mg/10 mg) Oral Pellets

Table of Content

Product Description

Lopinavir/ritonavir is a key antiretroviral for treating cases of pediatric HIV. Hence, the availability of appropriate child-friendly formulation of LPV/r is a necessity.

The currently available paediatric formulations of LPV/r are the oral solution for young children and paediatric tablets for older children.

The oral solution

  • Has an unpleasant taste.
  • Has a high alcohol concentration (42%), and contains propylene glycol, which is especially undesirable in children aged < 2 years.
  • Moreover, LPV/r solution requires refrigeration, making it challenging for storage, transportation, and use in resource-limited settings.
  • Dosing is based on body weight or surface area and requires accurate dose titration.
  • The paediatric tablet is still relatively large and should not be crushed because this decreases bioavailability by 40% versus whole tablets.

The above factors suggest that an alternative formulation of LPV/r, not requiring cold chain transportation and storage is urgently needed. An additional attribute would be simplified dosing based on weight bands.

LPV/r Oral Pellets are a novel formulation, available for oral administration as 40 /10 mg per capsule that can be administered by sprinkling over food. This capsule consists of mini-tabs of LPV/r produced by melt-extrusion technology.

Pharmacokinetics and Acceptability of LPV/r oral pellets

CHAPAS-2 (Children with HIV in Africa - Pharmacokinetics and Adherence of Simple Antiretroviral Regimens) study1

The CHAPAS-2 study assessed the pharmacokinetics and acceptability of a novel oral pellet formulation of LPV/r compared to the oral solution.

It was an open, randomized, phase I, 2-period crossover comparative bioavailability trial conducted in 77 infants (aged 3 to < 12 months) and children (aged 1 to < 13 years weighing < 25 kg) in Uganda as follows:

Cohort A included infants aged 3 to 12 months (n= 19)

Cohort B included children aged 1 to 4 years (n= 26)

Cohort C included children aged 4 to 13 years (n= 32)

24-hour intensive pharmacokinetic sampling was performed four weeks after enrollment, after which children switched formulations and sampling was repeated at week 8. Acceptability data were also collected.

Pharmacokinetics

LPV/r exposure from the oral pellets was comparable with the oral solution, but lower than tablets, with no significant differences in subtherapeutic concentrations.

Figure 1. Geometric mean LPV plasma concentrations in infants/children after intake of LPV/r. A, Cohort A (minitab sprinkle versus syrup in infants aged 3 to <12 months). B, Cohort B (minitab sprinkle versus syrup in children aged 1 to <4 years).

Acceptability1

Caregivers found oral pellets more acceptable than the oral solution for their infants/children, particularly for transportation and storage reasons. However, for older children already able to swallow tablets, these were more acceptable than the oral pellets.

Figure 3. Percentage reporting various problems for the different formulations. A, Cohort A (minitab sprinkle versus syrup in infants aged 3 to <12 months). B, Cohort B (minitab sprinkle versus syrup in children aged 1 to <4 years). C, Cohort C (minitab sprinkle versus tablet in children aged 4 to <13 years).

Thus, the LPV/r oral pellets represent an alternative formulation to the oral solution for young children unable to swallow tablets.

Dosage

Pediatric Patients2

LPV/r Oral Pellets should not be administered once daily in pediatric patients < 18 years of age.

LPV/r Oral Pellets should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained.

The following table lists the number of capsules containing LPV/r Oral Pellets 40 mg/10 mg to be administered twice-daily, using a simplified weight band-based approach.

Weight Band

Number of capsules containing Lopinavir and Ritonavir Oral Pellets 40 mg/10 mg* needed to prepare each dose

5 kg to less than 6 kg

2 capsules (80 mg) (twice daily)

6 kg to less than 10 kg

3 capsules (120 mg) (twice daily)

10 kg to less than 14 kg

4 capsules (160 mg) (twice daily)

14 kg to less than 20 kg

5 capsules (200 mg) (twice daily)

20 kg to less than 25 kg

6 capsules (240 mg) (twice daily)

* without concomitant efavirenz, nevirapine, amprenavir or nelfinavir

Administration

The capsules containing LPV/r oral pellets should not be swallowed whole, and should be administered with food, as described below: 2

  • Place a small amount of sweetened porridge (at room temperature) in a small bowl. The child should be able to easily consume this amount of porridge.
  • Count and remove the exact number of capsules required for the dose.

                                                                                                                                     

  1.Hold both ends of the capsule between your fingertips       2. Twist in opposite direction  and pull apart       3.All the pellets in the capsule should be sprinkled over the sweetened porridge

  • Repeat this step for the prescribed number of capsules per dose.
  • Ensure that all the porridge, with pellets, is swallowed by the child. The oral pellets SHOULD NOT be chewed or crushed.
  • This porridge/pellets mixture should be administered immediately and SHOULD NOT be stored for future use.
  • To ensure that no pellets are left behind in the mouth, give the child a drink of water.

Place in Therapy

With the higher risk of disease progression in young children, availability of appropriate child-friendly formulations is an imperative.3 LPV/r is considered by many as the first choice protease inhibitor (PI) for children.3 The World Health Organization (WHO) 2016 guidelines recommend the use of LPV/r along with abacavir /zidovudine plus lamivudine for children less than 3 years of age.4

Various pediatric studies have shown high virologic potency, an excellent toxicity profile and a high barrier to the development of viral resistance with LPV/r.5 Moreover, LPV/r based regimens have been found to be safe and effective in antiretroviral-naïve as well as antiretroviral-experienced HIV-infected children.6,7,8,9 However, the oral solution is associated with limitations such as need for a cold chain, high alcohol content and bitter taste. Whilst the paediatric tablets (LPV/r 100/25 mg) circumvent these disadvantages, they can be administered only to children who can reliably swallow.

The availability of this novel formulation of LPV/r oral pellets expands the scope of use of this potent antiretroviral, by providing a convenient alternative to the oral solution in infants and young children unable to swallow the paediatric tablet. 

Sequencing of ARV formulations for newborns starting treatment at around birth4

 

0-2 weeks

2 weeks-3 months

3-36 months

 

Preferred

 

AZT + 3TC + NVP

ABC or AZT + 3TC + LPV/r syrup

ABC or AZT + 3TC + LPV/r pellets*

 

Alternative

 

AZT + 3TC + NVP

ABC or AZT + 3TC + LPV/r pellets*

Special circumstances

AZT + 3TC + NVP

ABC or AZT + 3TC + RAL

         

* LPV/r pellets are indicated for children aged ≥ 2 weeks and weighing ≥ 5kgs

References

1.    Musiime V, et. al. The pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets, and syrups in african HIV-infected children. (J Acquir Immune Defic Syndr. 2014 Jun 1;66(2):148-54. doi: 10.1097/QAI.0000000000000135.)

2.    Prescribing Information of Lopinavir and ritonavir oral pellets 40 / 10 mg - Cipla

3.    Beatriz Larru Martinez, et. al. Novel strategies in the use of lopinavir/ritonavir for the treatment of HIV infection in children. (HIV/AIDS - Research and Palliative Care 2010:2 59–67.)

4.    WHO 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach.

5.    Ramos J. Boosted protease inhibitors as a therapeutic option in the treatment of HIV-infected children. (HIV Med. 2009 Oct;10(9):536-47. doi: 10.1111/j.1468-1293.2009.00728.x.)

6.    Violari A, et. al. Early Antiretroviral Therapy and Mortality among HIV-Infected Infants. (N Engl J Med 2008;359:2233-44)

7.    Chadwick EG, et. al. Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. (AIDS. 2011 Mar 13;25(5):643-9)

8.    Rudin C, et. al. Long-term safety and effectiveness of lopinavir/ritonavir in antiretroviral-experienced HIV-1-infected children. (Arch Dis Child 2010;95:478–481)

9.    Chadwick EG, et. al. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. (AIDS. 2008 Jan 11;22(2):249-55.)

Abridged Prescribing Information

Lopinavir and Ritonavir Oral Pellets (LPV/r) 40mg/10mg

COMPOSITION: Each capsule contains Lopinavir (40 mg) and Ritonavir (10 mg). Each container contains 120 capsules. INDICATION: LPV/r Oral Pellets 40mg /10mg is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients (14 days and older). DOSAGE AND ADMINISTRATION: LPV/r Oral Pellets should not be administered once daily in pediatric patients < 18 years of age. LPV/r Oral Pellets should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained. For full details on weight band based dosing and method of administration, please refer to page no.5 of this booklet. CONTRAINDICATIONS: LPV/r is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir. Co-administration of LPV/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions. Co administration of LPV/r is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. Please refer to the detailed prescribing information for further details.  WARNINGS AND PRECAUTIONS: Risk of Serious Adverse Reactions Due to Drug Interactions: LPV/r is a CYP3A inhibitor. Initiating treatment with LPV/r in patients receiving medications metabolized by CYP3A, or initiating medications metabolized by CYP3A in patients already receiving LPV/r, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of lopinavir and ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. Clinically significant adverse reactions from greater exposures of LPV/r. Loss of therapeutic effect of LPV/r and possible development of resistance. Consider the potential for drug interactions prior to and during LPV/r therapy; review concomitant medications during LPV/r therapy, and monitor for the adverse reactions associated with the concomitant medications. Please refer to the detailed prescribing information for further details.Toxicity in Preterm Neonates: LPV/r should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using LPV/r to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to LPV/r including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Pancreatitis: Pancreatitis has been observed in patients receiving LPV/r therapy, including those who developed marked triglyceride elevations. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and LPV/r and/or other antiretroviral therapy should be suspended as clinically appropriate. Hepatotoxicity: Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of LPV/r. Appropriate laboratory testing should be conducted prior to initiating therapy with LPV/r and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of LPV/r treatment. QT Interval Prolongation: Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of LPV/r could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval. PR Interval Prolongation: LPV/r prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. LPV/r should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients maybe at increased risk for developing cardiac conduction abnormalities. co-administration of LPV/r with PR prolongation drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. Diabetes Mellitus/Hyperglycemia: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Hepatic Impairment: LPV/r is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased. Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LPV/r. Lipid Elevations: Treatment with LPV/r has resulted in large increases in the concentration of total cholesterol and triglycerides Triglyceride and cholesterol testing should be performed prior to initiating LPV/r therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. Patients with Hemophilia: Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established. Resistance/Cross-resistance: Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in LPV/r-treated patients, it is unknown what effect therapy with LPV/r will have on the activity of subsequently administered protease inhibitors. ADVERSE REACTIONS: QT Interval Prolongation, PR Interval Prolongation, Drug Interactions, Pancreatitis, Hepatotoxicity. Postmarketing Experience: The following adverse reactions have been reported during postmarketing use of LPV/r: Body as a Whole: Redistribution/accumulation of body fat has been reported. Cardiovascular: Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes. Skin and Appendages: Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome and erythema multiforme. DRUG INTERACTIONS: LPV/r is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. LPV/r is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce lopinavir and ritonavir’s therapeutic effect Please refer to the detailed prescribing information for established and other potentially significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction. Drugs with No Observed or Predicted Interactions with LPV/r: Please refer to the detailed prescribing information for further details on no observed or predicted drug interactions. Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. LPV/r should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. STORAGE: Store below 30°C (86°F). Do not keep LPV/r Oral Pellets out of the container for longer than 2 weeks, especially in areas where there is a lot of humidity. Keep the container tightly closed.Keep LPV/r Oral Pellets and all medicines out of the reach of children.

For further details, please refer to the full prescribing information.

May 2015