Treatment of Nelfinavir-Associated Diarrhea?

Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Disclosures

December 27, 2001

Question

I take care of a 7-year-old boy with HIV infection whose viral load is presently well controlled on a regimen of stavudine, lamivudine, efavirenz, and nelfinavir. He continues to have watery stools (usually 3-4/day) despite optimal treatment with loperamide and a negative work-up for other etiologies. Do you know of any other strategies that I could use to manage this problem? I do not want to lower the dose of nelfinavir as I am afraid of losing the excellent antiviral potency of the current regimen. Thank you in advance for your response.

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Diarrhea with protease inhibitors (PIs)is not uncommon. During the development of nelfinavir, 32% of adult patients reported diarrhea.[1] Two pediatric investigations of nelfinavir-containing antiretroviral treatment regimens also demonstrated a high incidence of diarrhea,[2,3] ranging from 18% to 23%. The majority of patients develop diarrhea within 2 weeks of treatment initiation, and have resolution within 4-6 weeks. Most pediatric patients experienced diarrhea classified as Grade I (mild, defined only as soft stools).[4] Although nelfinavir-induced diarrhea is usually short-lived and often responsive to loperamide therapy, symptoms can continue in up to 70% of individuals.[5] This symptom is important to treat, as diarrhea has been found to be a negative predictor of survival in the Swiss HIV Cohort Study[6] by contributing to poor quality of life and poor adherence to medication regimens.

The exact underlying mechanism of PI-induced diarrhea is unknown,[7] and treatment is nonspecific and limited. Most information is contained in abstracts and case reports. For those patients refractory to loperamide therapy, 5 other options have been proposed: calcium, oat bran and psyllium, pancrealipase, SP-303, and diphenoxylate/atropine.

Perez-Rodriguez and colleagues[8] used calcium carbonate (Oscal; 500 mg twice daily) in 15 adult HIV-infected patients with nelfinavir-induced diarrhea. After 48 hours of therapy, 13 (87%) patients had normal stool as reported by survey and 100% noticed dramatic decreases in their symptoms. For pediatric patients, 45 mg/kg/day divided 2-4 times per day could be initiated, with a maximum of 65 mg/kg/day.[9] Symptoms should be relieved in a few days. If constipation occurs, the dose should be reduced. Abdominal pain and/or nausea may be a reason to discontinue calcium therapy.

Three abstracts have evaluated the use of oat bran and/or psyllium. Hoffman and colleagues[10] administered 1500 mg of oat bran tablets with each dose of medication to 51 HIV-infected adults with PI-associated diarrhea, 43% of whom were receiving nelfinavir. After 2 weeks of oat bran therapy, the frequency of diarrhea decreased from a mean grading score of 2 (4-7 stools per day) to a mean of 1.04 (<=3 stools per day), and 84% of patients reported their symptoms as being moderately or dramatically decreased. Hawkins and coworkers[11] conducted a telephone survey of 77 HIV-infected patients who had taken nelfinavir for at least 3 months, to assess the use and efficacy of powdered psyllium. Of the 77, 87% had experienced diarrhea and of those, 30% had tried psyllium for relief. Only approximately one half of these patients reported less frequent stools with the psyllium powder, and all reported poor taste tolerability. In light of this, Ronagh and associates[12] studied the fiber bar formulation of psyllium: 2 fiber bars were given 1 hour before bedtime for 2 weeks to 16 HIV-infected patients with PI-associated diarrhea. A total of 93% of these patients reported a decrease in diarrhea and better adherence. Both oat bran and psyllium have bloating and flatulence side effects. Equivalent doses for pediatric patients for oat bran, psyllium powder, and fiber bars are 500 mg 1-3 times per day, 0.5-1 teaspoonful 1-3 times per day, and 1 bar 1-3 times per day, respectively. If symptom relief is not seen after 2 weeks, an alternative therapy should be pursued.

Pancrealipase is a combination of pancreatic enzymes, lipase, protease, and amylase. It has been reported to increase the consistency and decrease the frequency of stools. Viokase and Ultrase MT 20 have both been used in HIV-infected patients with PI-associated diarrhea.[7,13] After failure of over-the-counter medications to treat diarrhea, 55 HIV-infected patients (36 on nelfinavir) were given 1 tablet of Viokase with each meal. Most patients had relief within 12 hours after initiation of Viokase, and diarrhea did not recur in 89% of patients.[7] Razzeca and colleagues[13] gave 26 HIV-infected patients with nelfinavir-induced diarrhea 2 tablets of Ultrase MT 20 with meals and snacks. Ninety-six percent of patients responded to therapy as assessed by a substantial decrease in number of stools per day. A pharmacokinetic analysis showed no drug interaction between Ultrase MT 20 and nelfinavir based on AUC, Cmax, and Tmax. Clinical efficacy was also assessed using viral load. All except 3 patients had a significant decrease in viral load, suggesting that Ultrase MT 20 has no detrimental effects on the clinical efficacy of nelfinavir.

SP-303 (SB Normal Stool Formula) is an herbal extract from a plant indigenous to South America Croton lechleri. It has been used for many years in the treatment of symptomatic diarrhea, and is thought to decrease secretion of chloride ions in gastrointestinal cells. A phase 2, randomized, double-blind, placebo-controlled trial in 51 HIV-infected patients was conducted with this compound, in which 500 mg of SP-303 or placebo was given every 6 hours for 4 days.[14] There was no statistically significant reduction in stool frequency between the treatment groups when comparing mean number of stools per day, although random regression analysis revealed a significant reduction in stool weight and frequency in the SP-303 treated group. No adverse events or abnormal laboratory findings were reported during the study. However, since clinical and adverse effect data in children are lacking, this should not be considered an option for pediatric patients.

Diphenoxylate/atropine (Lomotil) has also been suggested as treatment for PI-associated diarrhea at a dose of 2.5-5.0 mL up to 4 times pr day. However, in one report there was no response when Lomotil was used in 6 patients who were refractory to loperamide therapy.[13]

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP

In light of the above clinical data, and given the relative cost of the therapies (see Table), some general recommendations can be made for the treatment of pediatric patients who develop PI-induced diarrhea refractory to loperamide. Calcium therapy should be initiated at a maximum of 65 mg/kg/day in 2-4 divided doses. If diarrhea does not decrease after 2-3 days, psyllium or oat bran therapy may be used. Children's doses of psyllium powder should not exceed 1 teaspoonful 3 times daily, doses of fiber bars should not exceed 1 bar 3 times daily, and doses of oat bran should not exceed 1500 mg/day. If response is not seen within 2 weeks, pancreatic enzyme therapy should be offered next, although pancrealipase is expensive and efficacy data are limited. Ultrase MT 20 would be the preferred agent since pharmacokinetic and efficacy studies have shown no significant interaction with nelfinavir. The lowest dose needed to reduce diarrhea should be used: initiate 1 tablet with meals and snacks, and titrate to a maximum of 2 tablets per dose. If response is not seen within 2-3 days, Lomotil could be tried, although there is little evidence of its efficacy in PI-associated diarrhea, and it is expensive. Pediatric dosing of the liquid formulation should be 0.3-0.4 mg/kg/day divided 4 times per day. The use of SP-303 is not recommended, since it is not regulated by the Food and Drug Administration and there are no data in pediatric subjects.

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Agent Cost Cost per month (daily dose)
Calcium, 500-mg chew tabs $6.66 for 60 tablets $6.66 (500 mg bid)
Psyllium powder, 3.4 gm/dose $4.89 for 374 gm $4.89 (1 dose tid)
Psyllium fiber bars $3.66 for 14 bars (3.4 gm/bar) $22.00 (1 bar tid)
Viokase 8 tabs $35.25 for 100 tablets $35.25 (1 tablet with meals)
Ultrase MT 20 tabs $156.76 for 100 tablets $470.28 (2 tablets 5 times daily)
SP-303 tabs $35.99 for 60 tablets $54.00 (1 tablet tid)
Diphenoxylate/atropine liquid (2.5 mg diphenoxylate) $20.58 for 60 mL $308.70 (5 teaspoonsful/day for a 35-kg child*)
Diphenoxylate/atropine tabs (2.5 mg diphenoxylate) $22.01 for 30 tablets $110.05 (5 tablets/day)

* Source: Red Book, 2001

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